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.     

Puberty in girls: correlation of serum levels of gonadotropins, prolactin, androgens, estrogens, and progestins with physical changes.

Twenty-seven girls aged 8 to 18 were studied in a longitudinal prospective fashion. Serum samples were collected at 6 month intervals up to 4 years and radioassayed for hormones of pituitary, ovarian, and adrenal origin. A progressive elevation of luteinizing hormone (LH), follicle-stimulating hormone/FSH), estradiol (E2), dehydroepiandrosterone (DHA), and androstenedione (delta4) occurred during puberty and continued until menarche. The onset of puberty occurred concomitantly with an elevation of estrone (E1) dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DHAS), and 17-hydroxyprogesterone (17-OH-P). Prolactin (Prol) and progesterone (Prog) concentrations did not change during puberty until after menarche. After menarche, levels of LH and FSH were comparable with menstruating adult females. Concentrations of E2 and Prog were lower during the second half of the cycle among most regularly menstruating subjects than expected during the luteal phase. LH and Prog levels indirectly suggest that ovulation occurs in a few girls within months after menarche.     

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.     

Seventy-two hour infusions of LHRH in normal men: gonadotropin and testicular steroid responses.

Four normal male subjects received LHRH by continuous infusion for 72 hrs at 1.4 microgram/min. Mean basal LH was 7.7 +/- 1.0 mIU/ml, increased to a maximum of 120 +/- 22.7 mIU/ml, and then declined to levels between 28--34 mIU/ml for the last 30 hrs of infusion; FSH rose from 3.7 to 11.4 mIU/ml (p less than 0.05) at 16 hrs and then returned to baseline. Testosterone levels rose by 50% at 12 hrs, and remained elevated throughout with maximum values between 6.6 and 12 ng/ml. Estradiol-17beta levels were 26.2 +/- 4.7 pg/ml basally, rose to 104 +/- 8 pg/ml and while levels declined therafter, they were significantly above baseline throughout the 72 hrs. Plasma androstenedione and dehydroepiandrosterone levels also showed significant increases. By contrast, transient elevations in pregnenolone and 17-hydroxypregnenolone levels probably corresponded to the nomral morning rise in plasma levels of these steroids; 17-hydroxyprogesterone rose from 1.3 +/- 0.15 to 3.9 +/- 0.26 ng/ml at 12 hrs and remained elevated through the infusion. An increase in 17-hydroxyprogesterone:testosterone ratio was observed in all subjects. Thus, chronic LHRH infusion effected a persistent increase in endogenous LH with, in turn, prolonged stimulation of gonadal steroid secretion.     

TESTICULAR FUNCTION IN PREPUBERTAL MALE PSEUDOHERMAPHRODITISM

Testicular function was evaluated in forty-one prepubertal patients with male pseudohermaphroditism by determining serum concentrations of progesterone, 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, testosterone and dihydrotestosterone before and after stimulation with hCG and, in some instances, ACTH. Testosterone response to hCG was normal in all subjects. In one patient, a 4-year-old boy, a deficiency of 17,20-desmolase activity was diagnosed based on the coexistence of elevated levels of pregnenolone, 17-hydroxypregnenolone, progesterone and 17-hydroxyprogesterone and low levels of dehydroepiandrosterone and androstenedione. In three other patients enzymatic blocks were suspected but not confirmed. Congenital deficiency of enzymes necessary for testosterone biosynthesis is an uncommon aetiology of male pseudohermaphroditism.     

Hormonal pattern of adolescent menstrual cycles.

Serum FSH, LH, PRL, estradiol, pregnenolone, progesterone, 17-hydroxyprogesterone, androstenedione, testosterone, 5 alpha-dihydrotestosterone, and androsterone were measured radioimmunologically in 20 normal girls aged 13-17 yr. Samples were taken every day or every second day during one menstrual cycle. The cycles recorded could be divided into three groups. The first and oldest group consisted of 10 girls with a mean gynecological age (years since menarche) of 2.9 yr. The luteal phase was at least 11 days and the progesterone concentration was at least 5 ng/ml. The testosterone rise (mean, 55%) on the day of LH surge correlated well with the simultaneous progesterone rise (mean, 270%) and the following luteal progesterone secretion. A negative correlation was seen between the FSH concentration on days 3-4 of the cycle and the length of the follicular phase. The second group consisted of 4 girls who had a mean gynecological age of 1.5 yr. The luteal phase was of 4- to 8-day duration and the progesterone secretion was lower than in group I. The follicular phase testosterone concentration was lower in group II as compared to group I. No "periovulatory" testosterone increases were seen, although every cycle displayed an LH and FSH peak. The third group consisted of 6 girls with a mean gynecological age of 1.1 yr. These cycles were anovulatory, as the serum progesterone concentration never exceeded 1.0 ng/ml. In two cycles, signs of follicular maturation were seen. In the four others, the androgen levels tended to be elevated. In two cases, the testosterone and androstenedione concentrations were 2-4 times elevated from the beginning of these two cycles. Thus, the hormonal pattern of adolescent menstrual cycles is far from uniform. It is very likely that in addition to gonadotropins, estradiol and progesterone, androgens may also have a role in the development and maintenance of normal menstrual function in the female.     

Endocrine comparison of obese menstruating and amenorrheic women

10 examine the relationship between obesity and chronic anovulation, we compared basal serum LH, FSH, and PRL levels, determined at 20-min intervals, and basal C21 [progesterone, 17- hydroxyprogesterone , pregnenolone, 17-hydroxypregnenolone ( 17Pe ), and cortisol], C19 [testosterone (T), delta 4-androstenedione (A), and dehydroepiandrosterone] and C18 (estrone and estradiol) steroid hormone concentrations measured at 1- to 2-h intervals for a 24-h period in five normal weight cycling women (NC) and in two groups of weight-matched obese women. Five of the obese women were regularly cycling (OC), and six were amenorrheic (OA). Sex hormone-binding globulin (SHBG) and non-SHBG-bound T and estradiol concentrations were also measured in each woman. Compared to NC women, OC women had normal basal protein and steroid hormone concentrations, except for reduced 17Pe levels (P less than 0.05). Mean SHBG concentrations were reduced by approximately 30%, and non-SHBG-bound T was increased by 70%, although the differences were not significant. In addition, when six precursors of testosterone (pregnenolone, 17Pe , dehydroepiandrosterone, progesterone, 17-hydroxyprogesterone, and A) were considered together as a group and the data analyzed by the kappa 2 test, a reduction in basal levels of these precursors was found in OC women relative to those in NC women (P less than 0.005). In OA women, mean concentrations of SHBG were markedly reduced and those of total T, A, estrone, and non-SHBG-bound T were significantly increased compared to those in both NC and OC women. Mean 24-h concentrations of LH tended to be greatest and FSH lowest in this group, but were not significantly different from those in the other groups. The mean LH pulse frequency was significantly greater in OA than in OC women (P less than 0.05). Mean 24-h PRL and cortisol levels were also reduced in OA women relative to those in NC women. These data suggest the possibility of a compensatory decline in total T production in OC women in an attempt to maintain normal hormonal homeostasis; as a consequence, ovulation continues in a cyclic fashion. In OA women, such compensatory mechanisms are no longer operative. Instead, a central and/or peripheral defect, resulting in overproduction of androgen, may also exist and lead to anovulation in OA women. In conclusion, our data imply that obesity is not a primary factor causing chronic anovulation. However, obesity may aggravate an already existing subtle defect in some women and result in amenorrhea.     

Ketoconazole reverses hyperandrogenism in a patient with insulin resistance and acanthosis nigricans

We administered ketoconazole to a young woman with ovarian hyperandrogenism, insulin resistance, and acanthosis nigricans. While taking ketoconazole, her serum testosterone, androstenedione, dehydroepiandrosterone, and cortisol levels declined, while serum progesterone, 17-hydroxyprogesterone, and 11-deoxycortisol rose. Serum LH, FSH, and estradiol levels were intermittently higher during ketoconazole treatment, although LH and FSH responsiveness to GnRH did not change. Basal and stimulated serum insulin concentrations were high before and during ketoconazole therapy, while fasting glucose levels and glucose disappearance rate constants were normal throughout the study. A dramatic improvement in hirsutism occurred, and menses resumed after a 6-yr hiatus. Adverse drug effects or clinical evidence of adrenal insufficiency were not encountered. These results support a role for ketoconazole in the therapy of ovarian hyperandrogenism.     

Diurnal rhythms of luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol secretion before the onset of female puberty in short children

To investigate hormonal changes before the onset of female puberty, we measured LH and FSH in serum samples drawn every 20 min for 24 h and measured testosterone and estradiol hourly for 24 h. Seventeen girls (13 prepubertal and 4 early pubertal) of short stature, from 5.1-11.4 yr of age, participated in this study. LH and FSH were measured using a time-resolved immunofluorometric assay, and testosterone and estradiol were measured using a sensitivity RIA capable of detecting testosterone and estradiol concentrations of 10 and 2 pg/mL, respectively. Diurnal rhythms of LH, FSH, and testosterone were apparent in all subjects, including those aged 5-6 yr. Serum LH and FSH concentrations showed night-day variation in a pulsatile fashion. The serum testosterone concentration was elevated in the early morning in all subjects. The serum estradiol concentration was elevated in the early morning in 4 of 13 prepubertal subjects and all 4 early pubertal subjects. The diurnal pattern of the serum estradiol concentration was similar to that of the serum testosterone concentration. Mean 24-h LH and testosterone concentrations in prepubertal subjects who did not attain puberty for at least 1 yr were 0.07 U/L and 65 pg/mL, respectively, whereas those in prepubertal subjects who attained puberty within 1 yr (0.14 U/L and 106 pg/mL, respectively) were significantly higher. Furthermore, mean 24-h LH, FSH, testosterone, and estradiol concentrations increased with the onset of puberty. In conclusion, the diurnal rhythms of LH, FSH, and testosterone already exist at 5-6 yr of age, and serum LH and testosterone levels increase before the onset of puberty. These results suggest that preparation for the onset of female puberty may begin in 5- to 6-yr-old girls.     

Adrenal steroid secretion in girls with pseudoprecocious puberty due to autonomous ovarian cysts

To evaluate the role of adrenal steroids in pseudoprecocious puberty due to large ovarian follicular cysts, we studied the serum 17-hydroxyprogesterone response to a combination of dexamethasone suppression followed by iv ACTH administration in two girls and compared the results to those in girls with premature thelarche, normal prepubertal girls, and a girl with true precocious puberty. Although basal serum 17-hydroxyprogesterone levels were normal in all subjects, there was incomplete suppression of 17-hydroxyprogesterone with dexamethasone in the two girls with pseudoprecocious puberty and large ovarian cysts. The 17-hydroxyprogesterone response to ACTH was much greater in these girls (360 and 540 ng/dl) than in the girls with other types of precocious puberty (mean +/- SD, 71 +/- 15 ng/dl) or in normal prepubertal girls (80 +/- 20 ng/dl). The girls with large ovarian cysts had decreased gonadotropin responses to GnRH, which were reversed subsequent to removal of the cyst. Removal of the ovarian cysts also restored the dexamethasone suppressibility of serum 17-hydroxyprogesterone and abolished the progression of pubertal development. However, 17-hydroxyprogesterone responses to ACTH were still elevated (160 and 350 ng/dl). Preoperatively, both girls had increased levels of dehydroepiandrosterone sulfate, 16-hydroxydehydroepiandrosterone sulfate, and another unidentified steroid sulfate. These steroid sulfates were also found in the cyst fluid from the one patient from whom the fluid was obtained. These results suggest that steroid production by the adrenal gland may stimulate the development of small ovarian cysts (which may be present in normal prepubertal girls) into large ovarian cysts capable of causing gonadotropin-independent precocious puberty.     

Adrenal and gonadal steroids and pituitary response to LHRH in girls. I. Delayed puberty.

Plasma levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), dehydroepiandrosterone (DHA), dehydroepiandrosterone-sulphate (DHA-S), 17-hydroxyprogesterone (17P), androstenedione (A), testosterone (T), dihydrotestosterone (DHT) and estradiol (E2) were measured in basal conditions in eleven young women from 16 to 25 years of age characterized by delayed puberty. The gonadotropin response to LHRH (50 microgram iv) was also tested in these cases. The results, as far as gonadotropins and E2 are concerned, indicate that delayed pubertyin girls is a heterogeneous disorder: an impairment in the negative feedback between E2 and FSH coexists with a reduced ovarian response to endogenous gonadotropins. All cases showed evidence of a more or less pronounced delayed adrenarche, which was demonstrated by the markedly reduced levels of DHA-S and DHA (with the exception of this latter steroid in two cases with idiopathic hirsutism). Furthermore, the very low plasma progesterone (P) levels in all cases suggest the existence of impaired delta 5 - delta 4 isomerase activity in the adrenal cells. Despite the low levels of A and T, DHT is within the upper limits of the normal range in all cases.     

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.     

Partial 17, 20-desmolase and 17 alpha-hydroxylase deficiencies in a 16-year-old boy

Thirteen plasma steroids as well as ACTH, LH and FSH were measured by specific RIAs under basal and dynamic conditions in a 16-year-old boy (normal external genitalia, 46, XY karyotype) who presented slowness and unachievement of pubertal development. On the delta 4-pathway: basal levels of testosterone and dihydrotestosterone were low- with a normal ratio-, delta 4-androstenedione and 11 beta-hydroxyandrostenedione were in the low normal range. Meanwhile, 17 alpha-hydroxyprogesterone and progesterone levels were markedly elevated. On the delta 5-pathway: dehydroepiandrosterone was extremely low while 17 alpha-hydroxypregnenolone and pregnenolone were almost normal; dehydroepiandrosterone sulfate was subnormal while pregnenolone sulfate was normal. Cortisol, aldosterone were normal while ACTH was moderately increased. Basal and responsive levels of LH and FSH were markedly increased. ACTH stimulation induced a subnormal rise of cortisol and 11 beta-hydroxyandrostenedione, a low or absent rise of dehydroepiandrosterone, 17 alpha-hydroxypregnenolone, androstenedione and 17 alpha-hydroxyprogesterone contrasting with a marked rise of pregnenolone and progesterone. After hCG stimulation, responses were low for testosterone, extremely high for 17 alpha-hydroxyprogesterone with a normalisation of the 17 alpha-hydroxyprogesterone/progesterone ratio. Fluoxymesterone dramatically reduced the pathologically high basal levels of progesterone and 17 alpha hydroxyprogesterone. Dexamethasone induced only a minute decrease in the delta 4-progestagens, a marked decrease in pregnenolone, with a more than 80% reduction of 17 alpha- hydroxypregnenolone, dehydroepiandrosterone, dehydroepiandrosterone sulfate and androstenedione. These data suggest a defect involving the cytochrome P450 common to both 17 alpha-hydroxylase and 17, 20-desmolase activities.(ABSTRACT TRUNCATED AT 250 WORDS)     

Corticotropin-releasing hormone: a potent androgen secretagogue in girls with hyperandrogenism after precocious pubarche

CRH is an adrenal androgen secretagogue in men and has been proposed as a candidate regulator of adrenarche. CRH also affects androgen production by theca cells and may be involved in the pathogenesis of ovarian hyperandrogenism (OH). Precocious pubarche (PP) in girls can precede adolescent OH, a condition characterized by a high ovarian 17-hydroxyprogesterone (17-OHP) response 24 h after GnRH agonist challenge. In adolescent girls with a history of PP, we assessed the early androgen response to CRH, as well as the CRH effect on the late ovarian response to GnRH agonist. Within a randomized cross-over design, saline or CRH (human CRH 1 microg/kg x h in saline) was infused over 3-h (1100-1400 h) into 12 adolescent girls (age 17+/-2 yr; body mass index 21.4+/-0.9 Kg/m2) who had been pretreated with dexamethasone (1 mg at 0 h) and GnRH agonist (leuprolide acetate 500 microg sc at 0800 h = time 0). All adolescents had hirsutism, irregular menses, hyperandrogenemia, and hyperinsulinemia after PP. Serum LH, FSH, androstenedione, dehydroepiandrosterone (DHEA), and DHEA-sulfate (DHEAS) were measured at time 0, 3, 6, and 24 h, and ACTH and 17-OHP were measured at time 0, 6, and 24 h. ACTH concentrations at the end of saline or CRH infusions were less than 45 pg/mL; neither saline nor CRH infusions evoked early changes in 17-OHP levels. Within 3 h of CRH infusion, DHEAS increased by 46%, on average; androstenedione increased 2.5-fold and DHEA increased 5-fold duringCRH infusion (all P < 0.0001 compared with saline). There was no detectable CRH effect on the responses of LH, FSH, DHEA, DHEAS, 17-OHP, androstenedione, testosterone, and estradiol 24 h after GnRH agonist administration; five of 12 girls had elevated 17-OHP responses suggestive of OH. In conclusion, CRH was found to be a potent adrenal androgen secretagogue in adolescent girls with hyperandrogenism after PP. In this study, CRH failed to detectably affect the ovarian androgen response to gonadotropins.     

The influence of mammalian and avian gonadotropins on in vitro ovarian steroid synthesis in the turtle (Chrysemys picta).

The synthesis of steroids from 7α[³H]cholesterol and 7α[³H]pregnenolone by turtle ovarian tissues in vitro was studied. Pregnenolone, 17α-hydroxypregnenolone, progesterone, 17α-hydroxyprogesterone, androstenedione, testosterone, dehydroepiandrosterone, estrone, estradiol 17β, estriol, and 16-epiestriol were identified as products. All estrogens were detectable in incubates of preovulatory follicular tissue, but only small quantities of estrone were found in incubates of follicular tissue from postovulatory animals and luteal tissue. The effects of mammalian and avian gonadotropins on the metabolism of tritiated precursors were studied. Both mammalian and avian LH were stimulatory when conversion of cholesterol or pregnenolone to major steroid products was examined. In particular, enhancement of estrogen biosynthesis predominated in preovulatory follicular tissue, whereas increased progestin yield was the major effect in follicular and luteal tissue from postovulatory animals. The effects of FSH were minimal compared to the same dose of LH. Thus, a slight increase in estrogen yield was only noted when preovulatory follicular tissue was incubated with cholesterol and mammalian FSH, and neither mammalian nor avian FSH had an effect on pregnenolone conversion by follicles from postovulatory animals. Prolactin had no effect on luteal progesterone synthesis when used alone, but reduced the stimulatory effect of mammalian LH on progesterone synthesis. 11-Desoxycorticosterone was not found to be a product of the turtle ovary under normal conditions or after in vitro ACTH stimulation.     

Adrenal abnormalities in polycystic ovary syndrome

This study was undertaken to examine the role of adrenal androgen excess in the pathogenesis of polycystic ovary syndrome (PCOS) and, if such was present, to assess its reversibility using dexamethasone given in physiological dosage at night. Mean plasma testosterone (T), T/sex-hormone binding globulin (T/SHBG) ratio, androstenedione, and 17-OH-progesterone levels were elevated in the 19 patients studied. Plasma estrone values were elevated, whereas estradiol levels were normal. Plasma FSH was decreased and LH responsiveness to LHRH was exaggerated. Metyrapone, an 11-hydroxylase inhibitor, was administered at 2400 h to induce hypocortisolemia and compensatory ACTH secretion so that adrenal androgen and glucocorticoid responsiveness to endogenous stimulation could be examined. Plasma T, androstenedione, and 11-deoxycortisol responses to metyrapone were excessive in PCOS patients, thus indicating a specific adrenal abnormality. After 3 months treatment with dexamethasone, 0.5 mg at night, mean plasma T/SHBG and androstenedione declined to normal, and mean plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate declined to below normal. The mean estrone value was slightly lower during dexamethasone. Plasma LH responsiveness to LHRH was no longer significantly different from normal, but FSH was suppressed. During treatment androgen responsiveness to metyrapone stimulation was normal, whereas 11-deoxycortisol responsiveness was suppressed. Fifteen patients completed 3 months of treatment with dexamethasone. Of these, 10 resumed regular menstruation. The latter group had suppression of plasma T, T/SHBG, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate. Only plasma androstenedione fell significantly in the remainder. These observations support the hypothesis that, in at least some patients, PCOS develops in response to abnormal gonadotropin secretion induced by hyperestronemia occurring as a consequence of excessive adrenal androgen secretion.     

Comparison of clinical, ultrasonographic, and biochemical differences at the beginning of puberty in healthy girls born either small for gestational age or appropriate for gestational age: preliminary results

CONTEXT: There are limited and controversial data concerning puberty characteristics in girls born small for gestational age (SGA). OBJECTIVE: The objective of the study was to document clinical, ultrasonographic, and biochemical characteristics at the beginning of puberty in matched healthy girls born either SGA or appropriate for gestational age (AGA) recruited from the community. PATIENTS: Inclusion criteria were breast Tanner stage II and a body mass index between the 10th and 95th percentiles. INTERVENTIONS: Recruited subjects underwent a complete physical exam, bone age, and ultrasound measurements of the internal genitalia. Hormonal assessment included fasting early morning dehydroepiandrosterone sulfate, androstenedione, SHBG, inhibin-B, FSH, LH, estradiol (E2), 17-hydroxyprogesterone (17OH Prog), and testosterone. Thereafter, a GnRH agonist test (leuprolide 500 microg, sc) was performed with FSH and LH at time 3 and 24 h for E2, 17OH Prog, and testosterone. RESULTS: Sixty-five girls (35 AGA, 30 SGA) with a mean age of 9.9 +/- 1.03 (7.8-12.5) yr, similar bone age/chronological age (1.02 +/- 0.8 in AGA and 1 +/- 0.76 in SGA), median height of 1.35 +/- 0.06 cm, and similar waist to hip ratio were included. No differences in the presence of pubic hair, axillary hair, apocrine odor, or ultrasound measurements were found. SGA girls had increased baseline E2 as well as stimulated E2 and 17OH Prog. CONCLUSIONS: In a preliminary sample of lean, healthy girls recruited from the community born either SGA or AGA, we observed slight hormonal differences at the beginning of puberty. Longitudinal follow-up of this cohort will allow us to understand whether these differences are maintained and have a clinical impact in their pubertal development.     

Pathways of testosterone synthesis in decapsulated testes of mice.

In order to study the temporal relations in the biogenesis of testosterone, decapsulated testes of adult mice were incubated with carbon-14-labelled sodium acetate and attempts were made to isolate the most likely intermediates. Considerable quantities of radiochemically homogeneous squalene, lanosterol, cholesterol, testosterone and androstenedione, but no pregnenolone, progesterone, 17-hydroxypregnenoline, 17-hydroxyprogesterone, dehydroepiandrosterone, pregnenolone sulphate or dehydroepiandrosterone sulphate were isolated. The same pattern of incorporation was found when gradually increasing amounts of non-labelled pregnenolone, progesterone, 17-hydroxypregenenolone, 17-hydroxyprogesterone, dehydroepiandrosterone, dehydroepiandrosterone sulphate or testosterone were added to the system as "trapping agents" or when Leydig cell preparations rather than decapsulated testes were used. The presence of 10 mIU of HCG greatly enhanced the de novo formation of testosterone, androstenedione and 5alpha-dihydrotestosterone but did not change the pattern of acetate incorporation. Radioimmunoassays of the incubation medium with or without added HCG, and carried out at different periods of time indicated the presence of gradually increasing amounts of testosterone and androstenedione together with some 5alpha-dihydrotestosterone, whereas only trace amounts of pregnenolone, progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone and dehydroepiandrosterone were present. An analysis of the incubated testes revealed that the addition of HCG significantly enhanced the content of testosterone, androstenedione and 5alpha-dihydrotestosterone. Little or no increase was observed as far as pregnenolone, progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone or dehydroepiandrosterone were concerned. It is concluded that decapsulated testes of mice synthesize de novo testosterone from sodium acetate under conditions in which the formation of pregnenolone, progesterone, 17-hydroxypregnenolone, 17-hydroxyprogesterone, pregnenolone sulphate and 17-hydroxypregnenolone sulphate cannot be demonstrated.     

Sex steroid, gonadotropin, cortisol, and prolactin levels in healthy, massively obese women: correlation with abdominal fat cell size and effect of weight reduction

To examine hormonal status in obese, gynecologically normal women we studied 25 regularly menstruating, massively obese (mean weight, 120 kg) women participating in a weight reduction program and 25 age-matched normal weight (mean weight, 60 kg) women. Serum 17 beta-estradiol (E2), estrone (E1), androstenedione (A), dehydroepiandrosterone sulfate, testosterone, LH, FSH, PRL, and cortisol concentrations were measured during the follicular phase of the menstrual cycle. Waist to hip ratio and abdominal fat cell size were measured at the beginning of the study. The serum levels of E2 (P less than 0.04) as well as those of A, SHBG, and LH (P less than 0.002) were lower in the obese group. Consequently, the testosterone to SHBG ratio and the E1 to A ratio were higher and the LH to FSH ratio was lower in this group. Waist to hip ratio did not correlate with the levels of circulating hormones or SHBG, but an inverse correlation was found between abdominal fat cell size and A as well as the LH to FSH ratio in the nonhirsute women of the obese group. Subsequent to moderate weight reduction (13.2 kg), serum A and E1 levels (P less than 0.01) increased, and serum cortisol levels decreased (P less than 0.001). Thus, massive obesity is associated with abnormalities in hormonal balance in gynecologically symptomless women, there being an association between E1, E2, A, LH, cortisol, and relative weight and/or abdominal fat cell size.     

Lack of correlation between gonadotropin and adrenal androgen levels in agonadal children.

To evaluate the relationship between the secretion of gonadotropins and adrenal androgens, patients with gonadal agenesis were evaluated by (a) administering human luteinizing hormone (hLH) for 5 days with or without estrogen pretreatment to agonadal patients who had prepubertal LH levels; (b) correlating circulating gonadotropin levels with adrenal androgens in 45 patients; and (c) comparing adrenal androgens with gonadotropins after long-term administration of estrogen or androgens. Results are as follows: (a) No alteration in serum concentrations of dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DHAS), estrone (E1), testosterone (T), or in excretion of urinary 17-ketosteroid (17 KS) occurred after the administration of hLH. (b) No clearcut relationship between endogenous level of LH or FSH and DHA OR DHAS was demonstrated although a coincident increase of all hormones with age occurred. (c) Administration of estrogen to patients with gonadal agenesis did not affect their levels of DHA and DHAS although those patients given androgen developed higher DHAS, but not DHA, levels. Hence, increasing gonadotropin concentrations would not appear to be a primary etiologic factor in the maturation of the adrenal.