Hypothalamic-pituitary-ovarian response to clomiphene citrate in women with polycystic ovary syndrome

OBJECTIVE: To examine the hypothalamic-pituitary sites of clomiphene citrate (CC) action in women with polycystic ovarian syndrome (PCOS). DESIGN: Prospective controlled trial. PATIENTS, PARTICIPANTS: Seventeen women with PCOS and 9 normal-cycling women. INTERVENTIONS: Subjects with PCOS received CC, 150 mg/d for 5 days. MAIN OUTCOME MEASURES: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels and LH pulse characteristics and their response to gonadotropin-releasing hormone (GnRH, 10 micrograms) were examined before and after 3 days of CC in PCOS subjects during a 12-hour frequent sampling study (n = 8). Daily urinary estrone glucuronide and pregnanediol glucuronide levels after CC were compared with concentrations in normal-cycling women through one menstrual cycle. In another nine PCOS subjects, pituitary and ovarian hormonal cyclicity was monitored by daily blood sampling. RESULTS: Thirteen of 17 treated cycles were ovulatory with normal luteal phases. In the ovulatory cycles, serum LH, FSH, estradiol (E2), and estrone levels increased after CC. Luteinizing hormone pulse frequency was unchanged, but LH pulse amplitude increased significantly after CC. Both LH and FSH response to exogenous GnRH was significantly attenuated after CC treatment. In anovulatory cycles, serum LH, FSH, and E2 increased initially and then returned to baseline and remained unchanged for the ensuring 40 days. CONCLUSIONS: Clomiphene citrate-induced ovulation in women with PCOS is accompanied by increased secretion of LH and FSH with enhanced estrogen secretion. The increased LH pulse amplitude after CC, together with decreased pituitary sensitivity to GnRH, suggests a hypothalamic effect.     

Vessel boundary extraction based on a global and local deformable physical model with variable stiffness

BACKGROUND: Oligomenorrhea, defined as a menstrual cycle lasting 36 to 90 days, can be a normal condition in the first years after the menarche. When it persists or appears after a period of normal menstrual cycles, an underlying illness must be sought. AIM: To assess ovulation and causes of anovulatory cycles in women with oligomenorrhea, compared with causes of secondary amenorrhea. PATIENTS AND METHODS: One hundred one women of less the 35 years old, presenting with oligomenorrhea persisting 5 years after menarche or lasting more than two years after a period of normal menstrual cycles, were studied. Ovulation was studied measuring serial plasma progesterone during normal or induced (with intramuscular progesterone) menstrual cycles. RESULTS: Eighty nine percent of women had anovulatory oligomenorrhea. The main causes were polycystic ovarian disease in 51% and hypothalamic dysfunction in 31%. Thirty percent of women with secondary amenorrhea had polycystic ovarian disease and 14% had hyperprolactinemia. Women older than 20 years old or with more than 10 years of gynecological age had a higher frequency of polycystic ovarian disease and a lower prevalence of hypothalamic dysfunction. CONCLUSIONS: There is a high frequency of anovulatory oligomenorrheas. Therefore, this symptom deserves a thorough endocrinological assessment to uncover underlying diseases. Special attention must be paid to polycystic ovary syndrome, due to its importance in internal medicine as a risk factor for myocardial infarction, high blood pressure, and type 2 diabetes mellitus.     

Plasma hormones in clomiphene citrate therapy

Daily plasma follicle-stimulating hormone (FSH), luteinizing hormone (LH), estrone (E1), estradiol-17beta (E2), progesterone (P), androstenedione (A), and testosterone (T) were measured in six clomiphene citrate (Clomid) treated cycles. Three patients ovulated and 1 of them conceived during the study cycle. Three other patients failed to ovulate in spite of some evidence of ovarian response to clomiphene treatment in 2 of them. Plasma gonadotropin levels, of LH in particular, rose during the clomiphene therapy and reached a peak during Day 5 to Day 7 of therapy. Levels of plasma estrogens, both E1 and E2, gradually rose, reflecting follicular maturation in the ovary. When E2 reached a critical level as in the normal ovulatory cycle, it triggered an LH surge which consequently initiated ovulation. When the E2 level was inadequate or excessive, ovulation failed in spite of an LH surge. Following ovulation, plasma P rose and fell in a manner similar to the normal ovulatory cycle, with occasional values that exceeded the normal range. Levels of androgens, both A and T, rose during clomiphene therapy in some cases and T seemed to fluctuate in correlation with LH level. The possible local inhibitory influence of high E2 and T levels on follicular maturation in the ovary during clomiphene therapy is suspected in some cycles in which ovarian response was evident, but ovulation failed to occur.     

Effect of infarct artery patency on prognosis after acute myocardial infarction. The Survival and Ventricular Enlargement Investigators

In this study, adult male rats were injected intraperitoneally with a single dose of serotonin (5-hydroxytryptamine, 5HT; 10 mg kg-1 bodyweight) for 2 h or 18 h, or daily with graded doses of 5HT (0.1-10 mg kg-1) for four days before being killed. Serum and testicular interstitial fluid (IF) concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone and immunoreactive-inhibin were measured by radioimmunoassay, and one testis was removed for histological examination. At 2 h after a single injection, 5HT caused a significant inhibition of serum concentrations of LH and inhibin, recovered IF volume and intratesticular testosterone concentrations; testis weight and serum concentrations of testosterone and FSH were unaffected. At 18 h after injection, all parameters had returned to normal, with the exception of intratesticular testosterone concentration which remained lower than normal. The lowest 5HT dose (0.1 mg kg-1) had no effect on any parameter following four daily injections. At a dose of 1.0 mg kg-1 5HT, there was a four-fold increase in the concentration of serum LH, but testis weight, recovered IF volume, testosterone and inhibin concentrations and serum concentrations of FSH were not significantly affected. At the highest dose of 5HT (10 mg kg-1) after four daily injections, testis weight decreased, and IF volume increased nearly three-fold. Testis concentrations of inhibin and serum testosterone were reduced, whereas serum concentrations of both LH and FSH were elevated; intratesticular testosterone concentrations did not differ from controls. Only at the highest dose of 5HT was disruption to the seminiferous epithelium observed, with focal damage ranging in severity from increased degeneration of spermatogenic cell profiles, to complete loss of the germinal epithelium; however, many tubule profiles displayed completely normal spermatogenesis. The acute IF volume reduction and spermatogenic disruption in 5HT-treated rats were consistent with localized ischaemia due to constriction of the testicular arterial supply. The eventual increase in IF volume observed after 5HT treatment appeared to be secondary to the loss of germ cells. Although 5HT also inhibited pituitary LH release and Leydig cell steroidogenesis, these effects appeared to play only a minor role in the induction of spermatogenic damage.     

Androgen receptors in the anterior pituitary and central nervous system of the androgen "insensitive" (Tfm) rat: correlation between receptor binding and effects of androgens on gonadotropin secretion

The cytosol fractions of the anterior pituitary, hypothalamus, preoptic area and brain cortex of androgen "insensitive" (Tfm) rats possess androgen receptors. However, in the Tfm rats the androgen binding per mg protein was only 10-15% of that in the corresponding normal littermates (Nl). The physicochemical properties of the androgen receptors in the anterior pituitary of the Tfm rat were indistinguishable from those of the normal rat. Thus, no distinctive differences were observed with regard to electrophoretic mobility in 3.25% polyacrylamide gels, isoelectric point (pI=5.8), binding affinity (KD=1.5 X 10(-9)M), temperature stability, sulfhydryl dependence and steroid specificity. It is, therefore, likely that the very low androgen binding capacity by the anterior pituitary and the central nervous system is due to an extreme reduction in the receptor number rather than to the presence of abnormal receptors. Since in the Tfm animals the androgen receptor number is reduced by 85-90%, it is to be expected that very high doses of androgens would be required to achieve hormonal effects. In fact, low doses of 5alpha-dihydrotestosterone propionate (50 mug/100 g body weight) given sc daily for 12 days had no effect on serum levels of LH and FSH. However, very high doses (2 mg/100 g body weight) of testosterone propionate and 5alpha-dihydrotestosterone propionate, which maintained circulating androgen levels above 20 ng/ml, significantly reduced serum gonadotropin levels in castrated Tfm rats. In normal littermates both low and high doses of the androgens suppressed gonadotropin secretion to low levels. These findings strongly indicate that androgen receptors are essential to androgen action on the anterior pituitary and central nervous system in the rat. The serum levels of testosterone (7.7+/-0.15 (SE) ng/ml) and 5alpha-dihydrotestosterone (0.37+/-0.06 ng/ml) were significantly higher in intact Tfm rats than in normal littermates (2.6+/-0.03 and less than 0.1 ng/ml, respectively). The failure of the elevated concentrations of serum androgens to reduce the high serum levels of LH and FSH in intact Tfm rats is most likely due to the extreme reduction of the androgen receptor number and the consequent insufficient hypothalamic and/or pituitary response to androgens.     

Multiple metachronous metastasis of adenocarcinoma of the kidneys in crossed ectopy with fusion

OBJECTIVE: Hyperandrogenism in patients with polycystic ovary syndrome has been shown to correlate with hyperinsulinaemia of insulin resistance. We have investigated if basal levels of insulin and the response to the intravenous administration of glucagon can reveal insulin resistance in patients with polycystic ovary syndrome. PATIENTS: Nine obese (BMI > 25 kg/m2) and nine non-obese (BMI 19-25 kg/m2) women with PCOS, chosen from a population of 91 women attending the infertility clinic, and 19 normally cycling women (seven obese, 12 non-obese) were studied. Oligo or amenorrhoea, hirsutism, and 12 or more follicles in a given ovary were selection criteria. MEASUREMENTS: Glucagon, 1 mg, was given intravenously to 18 of the 91 women and to the control subjects. Blood was taken at -5, 0, 5, 10 and 15 minutes for measurements of integrated areas under the response curve for insulin, C-peptide and glucose, respectively. Basal blood samples were drawn for fasting insulin, C-peptide, glucose, testosterone, sex hormone-binding globulin (SHBG), free fatty acids and IGF-I measurements. The free androgen index was calculated according to the formula FAI = testosterone x 100/SHBG. RESULTS: There were no significant differences in maximal increment and area under the response curve for glucose, C-peptide and insulin. FAI was significantly higher in all patients with features of polycystic ovary syndrome. However, fasting insulin levels were significantly higher only in obese patients when compared with obese control subjects and lean patients. CONCLUSIONS: The administration of 1 mg glucagon i.v. did not distinguish patients with polycystic ovary syndrome from control subjects. The mild insulin resistance of polycystic ovary syndrome is related only to obesity and is therefore unlikely to play an important role in the hyperandrogenism associated with the syndrome.     

Effect of ethinyl estradiol-dienogest combination on serum androgen concentrations

Antiandrogens or progestins with an antiandrogenic component usually have only a weak antigonadotropic activity. It is thus possible that the antiandrogenic effect on the cellular level is cancelled or at least reduced by an increased ovarian androgen production. The aim of the four submitted clinical studies of the progestin and antiandrogen dienogest alone (0.5-2 mg/day) or of a combined regimen of ethinylestradiol (0.03 mg) plus dienogest (2 mg) (EE/DNG) was to examine the influence on the serum androgen and SHBG concentrations as well as on the serum FSH, LH, progesterone and 17 beta-estradiol concentrations in young women. Like the progesterone derivatives, dienogest has a relatively low antigonadotropic activity. Inhibition of ovulation is mainly produced by peripheral mechanisms such as the reduction of preovulatory 17 beta-estradiol secretion. Dienogest alone has no significant effects on the serum SHBG and androgen concentrations. Unlike this, the combination of EE plus DNG markedly increases SHBG concentrations (to 2.1-3.7 fold the basal levels). The decrease in serum androgens with total testosterone (by 17 and 40%), free testosterone (by 48 and 54%) and dehydroepiandrosterone sulfate (by 51%) corresponds to the values shown in the literature for other oral contraceptives with modern progestins. EE/DNG does not affect the serum concentrations of 5 alpha-dihydrotestosterone (DHT), although the marker of the peripheral transformation from T to DHT, androstanediol glucuronide, is distinctly reduced (by 38%). In a double-blind comparison no differences are found between EE/DNG and a regimen combining 0.02 mg of ethinylestradiol and 0.150 mg of desogestrel. Solely the SHBG concentrations, with EE/DNG, as expected, are significantly higher. In a sequential regimen, dienogest, chlormadinone acetate and desogestrel (progestins without binding to SHBG) enhance the inhibitory effect of ethinylestradiol sulfonate on free testosterone, whereas norethindrone acetate and levonorgestrel (progestins with a strong binding to SHBG) reduce this effect of the estrogen significantly. These results exclude the possibility that the very distinct antiandrogenic effect of dienogest on a cellular level is neutralised or reduced by an increased systemic supply of androgen.     

Serum total renin is elevated in women with polycystic ovarian syndrome

OBJECTIVE: To examine the serum total renin in women with polycystic ovarian syndrome (PCOS) and in controls. SETTING: Outpatient clinic of reproductive endocrinology at Turku University Central Hospital, Turku, Finland. PATIENTS: Forty-four oligomenorrheic women with PCOS (body mass index [BMI] 18.0 to 49.0 kg/m2) and 25 control women with regular menstrual cycles (BMI 18.0 to 53.5 kg/m2). MAIN OUTCOME MEASURES: The concentrations of total renin, LH, FSH, T, androstenedione (A), sex hormone-binding globulin (SHBG), and insulin in serum. RESULTS: The concentration of total renin in serum was higher in PCOS women than in healthy women independently of BMI, age, or serum insulin. The serum total renin measurement discriminated PCOS patients and control women to a similar extent as the previously used hormonal parameters (LH:FSH, T, A, and T:SHBG) as judged by receiver-operating characteristic analysis. Positive correlations were found between the serum total renin level and LH concentration, LH:FSH ratio, T and A levels, and T:SHBG ratio. Analysis of serum total renin in PCOS patients during oligomenorrhea and after menstruation did not reveal any significant changes. CONCLUSIONS: The elevated concentration of serum total renin suggests an enhanced activity of ovarian renin-angiotensin system in PCOS. The determination of serum total renin may provide a novel tool in the diagnostics of PCOS, because its serum level is elevated in PCOS women independently of BMI and serum insulin.     

Hypergonadotropic secondary amenorrhea: clinical analysis of 126 cases

OBJECTIVE: To study the etiology and early diagnosis of hypergonadotropic amenorrhea and to explore the appropriate treatment for preserving their reproductive function. METHODS: 126 cases of secondary amenorrhea with serum follicular stimulating hormone (FSH) levels > or = 40 IU/I, were analysed. Their clinical manifestations, karyotypes, ovarian morphology and histology, reproductive hormone assays, and responses to estrogen therapy and ovulation induction were studied. RESULTS: 6 cases presented with histories of ovarian surgery, radiotherapy or chemotherapy. Among the other 120 cases, 18 manifested amenorrhea before or at 25 years of age, 102 developed amenorrhea after age 25. In the former group, 16 (88.9%) showed unilateral or bilateral gonadal dysgenesis, and the other 2(11.1%) were defined as resistant ovaries. Abnormalities of sex chromosome karyotype occurred in 44.4% (8/ 18). In the latter group, 68 underwent laparotomy or laparoscopy examination. Morphological and histological examinations of both ovaries showed atrophic ovaries in all cases accompanied by 30.9% (21/ 68) unilateral gonadal dysgenesis; sex chromosomal abnormality was found in only one with no sexual immaturation. The efficacy of estrogen treatment was significantly better among cases with amenorrhea less than 1 year as compared with those longer than 1 year. Clomiphene challenge test given to 8 cases during their irregular menstrual stages produced an elevation of FSH levels to > 20 IU/I. without any response of estradiol secretion. CONCLUSIONS: The earlier estrogen therapy is initiated, the greater possibility of pregnancy will be achieved in cases suffering from hypergonadotropic amenorrhea. The clomiphene challenge test may provide evidence of waning ovarian function for early diagnosis.     

An inactivating mutation of the luteinizing hormone receptor causes amenorrhea in a 46,XX female

Hypergonadotropic hypogonadism is characterized by decreased gonadal function due to the inability of the gonads to respond to pituitary gonadotropins. Hypergonadotropic hypogonadism in females has many causes, among which are ovarian dysgenesis and abnormalities of the ovarian receptors for the pituitary gonadotropins. We evaluated a woman who presented with amenorrhea due to hypergonadotropic hypogonadism, but who had structurally normal ovaries. She is a sister of two previously identified 46,XY male pseudohermaphrodites with Leydig cell hypoplasia. Injection of hCG did not cause any change in plasma levels of estradiol or progesterone, suggesting complete ovarian resistance to LH. Analysis of the DNA sequence of the LH receptor gene revealed that the patient is homozygous for the same single base change as her two brothers. This mutation causes substitution of an alanine residue by a proline at position 593. In vitro analysis of the mutant LH receptor in cultured human embryonic kidney 293 cells documented that the receptor is unable to stimulate adenylyl cyclase in response to hCG. Plasma levels of estradiol and progesterone were low, whereas LH and FSH levels were increased. On histological analysis of the ovary, follicles were seen at all developmental stages. Nonetheless, primary amenorrhea had been present for 5 yr, and repeated measurements of plasma estradiol and progesterone indicate that ovulation does not occur. These results document the existence of inherited LH resistance as a cause of primary amenorrhea in women. The combined clinical and molecular observations are consistent with previous experimental data suggesting that in humans, LH is necessary for ovulation but follicular maturation can occur in the presence of FSH alone.     

Treatment of hyperandrogenic manifestations in polycystic ovary syndrome

Etiopathogenesis of the polycystic ovarian disease is not clarified. Therefore, optimum therapy of hyperandrogenic syndromes, menstrual and fertility disorders pose a difficult problem. Sequential therapy with estrogens and progestagens is of value in young women, who are not planning to conceive in order to reduce hirsutism and regulate menses. A reduction of hirsutism, acne and seborrhea is produced within 3 months. However, cessation of the treatment produces the symptoms of excessive androgen production. Another method is therapy with antiandrogens, especially cyproterone acetate. This drug inhibits androgens biosynthesis and has also peripheral activity. Spironolactone is another antiandrogen frequently used, but it is known as a primarily diuretic agent. It acts primarily at the androgen receptor sites. Other antiandrogens such as ketoconazole and flutamide are used less frequently. It has been shown, that cimetidine--known H2 receptor inhibitor--also decreases the symptoms of hyperandrogenism. However, cimetidine has not been used for the treatment of polycystic ovarian disease. In cases of enzymatic defects in adrenocortical steroido-synthesis glucocorticoids are used, mainly low doses of triamcinolone and dexamethasone. Other therapies are preferred in case of polycystic ovarian disease in women, who want to conceive. Clomiphene citrate and gonadotropins, mainly FSH, are used to induce ovulation. If pharmacotherapy does not produce ovulation, wedge resection of the ovaries must be performed.     

Follicular fluid hormone concentrations after ovarian stimulation using gonadotropin preparations with different FSH/LH ratios. I. Comparison of an FSH-dominant and a purified FSH preparation

OBJECTIVE: A small amount of LH is necessary for 17beta-estradiol production in the ovarian follicle. Human menopausal gonadotropin (hMG) contains equal amounts of FSH and LH activity, whereas recombinant FSH is a gonadotropin preparation without LH. The aim of the present randomized study was to investigate whether ovarian stimulation treatment with recombinant FSH or hMG resulted in different steroidal composition of follicular fluid. METHODS: Antral fluid from mature follicles was collected in in vitro fertilization cycles and concentrations of testosterone, androstenedione, estrone, estradiol, progesterone, FSH, and LH were determined. Seven patients (27 samples) were treated with hMG, 6 patients (22 samples) with recombinant FSH. RESULTS: Androgen, estrogen, progesterone, and FSH concentrations in follicular fluid tended to be lower in the group treated with recombinant FSH, but the variation was large and differences were statistically not significant. CONCLUSION: Treatment with a gonadotropin preparation containing no LH resulted in adequate androgen and estrogen levels in antral fluid of the ovarian follicle in women with normal endocrine profiles, even during pituitary suppression by a GnRH agonist. Apparently, the amount of endogenous LH was sufficient for steroid production within the follicle.     

Menstrual abnormalities in women with Cushing's disease are correlated with hypercortisolemia rather than raised circulating androgen levels

Menstrual irregularity is a common complaint at presentation in women with Cushing's syndrome, although the etiology has been little studied. We have assessed 45 female patients (median age, 32 yr; range, 16-41 yr) with newly diagnosed pituitary-dependent Cushing's syndrome. Patients were subdivided into 4 groups according to the duration of their menstrual cycle: normal cycles (NC; 26-30 days), oligomenorrhea (OL; 31-120 days), amenorrhea (AM; > 120 days), and polymenorrhea (PM; < 26 days). Blood was taken at 0900 h for measurement of LH, FSH, PRL, testosterone, androstenedione, dehydroepiandrosterone sulfate, estradiol (E2), sex hormone-binding globulin (SHBG), and ACTH; cortisol was sampled at 0900, 1800, and 2400 h. The LH and FSH responses to 100 micrograms GnRH were analyzed in 23 patients. Statistical analysis was performed using the nonparametric Mann-Whitney U and Spearman tests. Only 9 patients had NC (20%), 14 had OL (31.1%), 15 had AM (33.3%), and 4 had PM (8.8%), whereas 3 had variable cycles (6.7%). By group, AM patients had lower serum E2 levels (median, 110 pmol/L) than OL patients (225 pmol/L; P < 0.05) or NC patients (279 pmol/L; P < 0.05), and higher serum cortisol levels at 0900 h (800 vs. 602 and 580 nmol/L, respectively; P < 0.05) and 1800 h (816 vs. 557 and 523 nmol/L, respectively; P < 0.05) and higher mean values from 6 samples obtained through the day (753 vs. 491 and 459 nmol/L, respectively; P < 0.05). For the whole group of patients there was a negative correlation between serum E2 and cortisol at 0900 h (r = -0.50; P < 0.01) and 1800 h (r = -0.56; P < 0.01) and with mean cortisol (r = -0.46; P < 0.05). No significant correlation was found between any serum androgen and E2 or cortisol. The LH response to GnRH was normal in 43.5% of the patients, exaggerated in 52.1%, and decreased in 4.4%, but there were no significant differences among the menstrual groups. No differences were found in any other parameter. In summary, in our study 80% of patients with Cushing's syndrome had menstrual irregularity, and this was most closely related to serum cortisol rather than to circulating androgens. Patients with AM had higher levels of cortisol and lower levels of E2, while the GnRH response was either normal or exaggerated. Our data suggest that the menstrual irregularity in Cushing's disease appears to be the result of hypercortisolemic inhibition of gonadotropin release acting at a hypothalamic level, rather than raised circulating androgen levels.     

Changes in ovarian function and gonadotropin secretion preceding the onset of nutritionally induced anestrus in Bos indicus heifers

The aim of this study was to monitor endocrine and ovarian changes immediately preceding the onset of nutritionally induced anestrus. Daily blood samples were obtained from 14 postpubertal heifers for one estrous cycle (initial estrous cycle). Subsequently, heifers designated "restricted" were given a limited diet (n = 9), and daily blood samples were obtained for approximately 21 days preceding onset of anestrus (anovulatory cycle). Controls were allowed ad libitum dietary intake (n = 5), and daily blood samples were collected for a complete estrous cycle during a time period that coincided with that preceding onset of anestrus in restricted heifers. Plasma samples were assayed for LH, FSH, progesterone, and estradiol-17 beta. The ovaries of all heifers were examined daily using transrectal ultrasonography from the initial until the final or anovulatory estrous cycles to determine changes in growth of follicles and corpora lutea. Anestrus was defined as failure of ovulation of the dominant follicle following luteolysis. When anovulatory and initial estrous cycles in restricted heifers were compared, mean concentrations of LH were lower (p < 0.01), and diameters of dominant follicles were smaller (p < 0.01); mean concentrations of estradiol-17 beta were also lower in the three days following luteolysis (p = 0.06), but concentrations of FSH appeared to be higher (p = 0.003); maximum diameters of corpora lutea were smaller (p < 0.001), but duration of luteal phases and concentrations of progesterone preceding luteolysis were similar (p > 0.10). In controls, no differences were found between estrous cycles for any of these variables. It is concluded that failure of ovulation, following reduced dietary intake, resulted from insufficient circulating LH to stimulate maturation of the ovulatory follicle.     

Hirsutism

Hirsutism (increased masculine-type sexual hair growth) is to be distinguished from hypertrichosis (generalized increase of body hair) and from virilism (organ changes tending towards masculinity) in which marked hormonal changes are alwasy observable. Hirsutism depends on age, race, heredity, hairfolicle sensitivity to testosterone, and on circulating testosterone and its precursors. The main source of testosterone and androstanedione formation is not the adrenal cortex, as previously assumed, but, as catheterization has demonstrated, the ovary. Mild forms can best be treated externally by plucking, shaving or electrolysis. In forms associated with amenorrhea the amenorrhea responds to corticoids but over a prolonged period of treatment the maximum regression of hirsutism is one-third. Good results are obtainable by reverse-sequence therapy with the competitive androgen antagonists cyproterone acetate and ethinyl estradiol (100 mg cyproterone acetate from 5th-14th day of menstrual cycle and 50 mug ethinyl estradiol from 5th-21st day). This therapy is however costly and not without side effects; it should therefore be used only for particularly troublesome cases.     

Effect of clomiphene citrate on gonadotropin responses to LRH administration in secondary amenorrhea and oligomenorrhea

Clomiphene citrate was administered to 17 patients with either secondary amenorrhea or oligomenorrhea to study its effect on hypothalamic-pituitary response. Measurement of pulsatile gonadotropin output was accomplished utilizing samples collected every 20 minutes for 6 to 8 hours before and after clomiphene administration. Response to 100 mug synthetic luteinizing hormone releasing hormone (LRH) was measured at the end of the sampling period. Patients with polycystic ovarian disease who ovulated showed increased baseline FSH and LH, decreased peak LH, and a decrease in the percentage increase over baseline for both LH and FSH. On patient wil clinical anorexia nervosa responded to clomiphene as an estrogen, with lowered baseline LH and FSH values. Patients with resolving anorexia responded to clomiphene as an antiestrogen, with increased baseline gonadotropins, and decreased gonadotropin peak values. A patient with a surgically treated chromophobe adenoma showed no change in parameters measured before and after clomiphene administration. Baseline and pulsatile LH output appear to reflect the tonic output of gonadotropin as affected by estrogen acting in a negative feedback system, and the peak response to LRH administration, the response to the positive feedback of estrogen. Thus, LRH stimulation in clomipheneresistent patients may be of value in diagnosing the site and degree of the defect and aid in improving therapy.     

The follicle-stimulating hormone (FSH) threshold/window concept examined by different interventions with exogenous FSH during the follicular phase of the normal menstrual cycle: duration, rather than magnitude, of FSH increase affects follicle development

According to the threshold concept, FSH concentrations need to surpass a distinct level to stimulate ovarian follicle growth. The window concept stresses the significance of a limited duration of elevated FSH levels above the threshold for single dominant follicle selection. The aim of this study was to investigate effects on follicle growth of increased FSH levels, differing in duration and magnitude of elevation, during the follicular phase. Twenty-three normo-ovulatory (cycle length, 26-31 days), young (age, 20-31 yr) women volunteered for this study. In all subjects a series of daily transvaginal sonography scans of the ovaries and blood sampling [for FSH and estradiol (E2) determinations] were performed during two consecutive cycles. The first study cycle (control cycle) started 10 days after urinary assessment of the LH surge in the preceding cycle (DayLH) and was concluded on the day of ovulation assessed by transvaginal sonography scans. The second series of daily monitoring (intervention cycle) started 10 days after DayLH in the control cycle. After randomization, subjects received either 375 IU urinary FSH, s.c., as a single injection on Day(LH+14) (group A; n = 11) or 75 IU daily from Day(LH+19) until Day(LH+23) (group B; n = 12). In group A, FSH levels increased on the day after injection to a median concentration of 10.1 IU/L, which was 1.9 times higher (P < 0.01) than levels on matching days during the control cycle. Concentrations returned to basal levels 3 days after injection. In group B, a moderate elevation of FSH concentrations (15% increase; P < 0.05) was observed compared to levels during the control cycle. In group A, E2 concentrations increased (P = 0.03) 1 day after FSH injection and returned to baseline levels within 2 days. In group B, E2 levels started to increase after the first injection of FSH and remained significantly higher (P < 0.01) during the following 5 days compared to those on matching days in the control cycle. Compared to matching days in the control cycle an increased number of follicles 8-10 mm in size was found in group A (P < 0.01) during the period from Day(LH+14) until Day(LH+19), without an increase in follicles 10 mm or larger thereafter. In contrast, in group B, the numbers of both 8- to 10-mm and 10-mm or larger follicles were higher during the period from Day(LH+19) until Day(LH+24) in group B (P = 0.02 and P < 0.01, respectively). Results from the present study suggest that a brief, but distinct, elevation of FSH levels above the threshold in the early follicular phase does not affect dominant follicle development, although the number of small antral follicles did increase. In contrast, a moderate, but continued, elevation of FSH levels during the mid to late follicular phase (effectively preventing decremental FSH concentrations) does interfere with single dominant follicle selection and induces ongoing growth of multiple follicles. These findings substantiate the FSH window concept and support the idea of enhanced sensitivity of more mature follicles for stimulation by FSH. These results may provide the basis for further investigation regarding ovulation induction treatment regimens with reduced complication rates due to overstimulation.     

Follicular development and hormonal levels following highly purified or recombinant follicle-stimulating hormone administration in ovulatory women and WHO group II anovulatory infertile patients

PURPOSE: Our purpose was to compare ovarian performance and hormonal levels, after ovulation induction, in both normal ovulatory women undergoing intrauterine insemination (group 1) and World Health Organization (WHO) group II anovulatory infertile patients (group 2), using two different gonadotropin drugs. METHODS: Patients (n = 20 per group) were treated during consecutive cycles, using the same stimulation protocol, with highly purified urinary FSH (HP-FSH) in the first treatment study cycle and recombinant FSH (rFSH) in the second one. Patients in group 1 were treated according to a late low-dose technique, and WHO group II anovulatory patients (group 2) received chronic low-dose FSH therapy. RESULTS: Compared with HP-FSH, treatment with rFSH in group 2 required significantly less ampules of drug to induce follicular development but resulted in significantly higher plasma levels of estradiol and inhibin A on the day of human chorionic gonadotropin injection. No differences were found when both treatment modalities were compared in group 1. CONCLUSIONS: rFSH is more efficacious than urinary HP-FSH for ovulation induction in WHO group II anovulatory infertile patients as assessed by follicular development, hormonal levels, and the amount of FSH required.     

Expression of Shaker-type voltage-gated potassium channel genes in the guinea-pig

PROBLEM: Inhibin A concentrations in serum may reflect the ovarian granulosa cell compartment. To characterize the correlation between ovarian function after gonadotoxic chemotherapy for Hodgkin's or non-Hodgkin's lymphoma in young women, the immunoreactive inhibin A concentrations in the sera of these patients was measured before, during, and after the gonadotoxic chemotherapy. METHOD OF STUDY: A prospective clinical protocol was undertaken in 20 cycling women with lymphoma, aged 15-40 years. A monthly injection of depot D-TRP6-GnRH-a (Decapeptyl CR, Ferring) was administered from before starting the chemotherapy until its conclusion, up to a maximum of six monthly injections. Most of the patients were treated with the mustargen-oncovin-procarbazine-prednisone (MOPP)/actinomycin D-bleomycin-vincristine (ABV) chemotherapy combination; 13 with and 7 without radiotherapy. A hormonal profile [follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17-beta-estradiol (E2), testosterone (T), progesterone (P4), insulin-like growth factor (IGF)-1, IGF-BP3, and prolactin (PRL)] was taken before starting the gonadotropin-releasing hormone agonist (GnRH-a)/chemotherapy co-treatment and monthly thereafter until resuming spontaneous ovulation and menstrual cyclicity. This group of prospectively treated lymphoma patients was compared with a control group of 22 regularly cycling women who had been treated with chemotherapy (mostly MOPP/ABV) with or without radiotherapy for Hodgkin's or non-Hodgkin's lymphoma. Inhibin A immunoactivity developed by Nigel Groome was measured by an enzyme-linked immunoadsorbent assay (ELISA) commercial kit (Serotec). RESULTS: Whereas all but one (40 years of age) of the surviving patients in the GnRH-a/chemotherapy co-treatment group resumed spontaneous ovulation and menses within 6 months, only one half of the patients in the "control" group (chemotherapy without GnRH-a co-treatment) resumed ovarian function and regular cyclic activity (P < 0.05). The remaining 50% experienced premature ovarian failure (POF). Temporarily increased FSH concentrations were experienced by approximately one third of the patients resuming cyclic ovarian function, suggesting a reversible ovarian damage in a larger proportion of women than those experiencing POF. The inhibin A immunoactive concentrations decreased during the GnRH-a/chemotherapy co-treatment but increased to normal levels in patients who resumed regular ovarian cyclicity, and/or spontaneously conceived, as compared to low levels in menopausal women and those who had developed POF. CONCLUSIONS: If these preliminary data are consistent in a larger group of patients, inhibin A concentration may serve as a prognostic factor for predicting the resumption of ovarian function, in addition to the levels of FSH, LH, and E2.     

Prevention of irreversible chemotherapy-induced ovarian damage in young women with lymphoma by a gonadotrophin-releasing hormone agonist in parallel to chemotherapy

To examine whether the concomitant administration of a gonadotrophin-releasing hormone agonist (GnRHa) during combination chemotherapy to young women with lymphoma may facilitate preservation of gonadal function, a prospective clinical protocol was undertaken in 18 cycling women with lymphoma, aged 15-40 years. Thirteen patients suffered from Hodgkin disease (HD) and 5 from non-Hodgkin lymphoma. After informed consent a monthly injection of depot D-TRP6-GnRHa was administered for a maximum of 6 months starting prior to chemotherapy. Most of these patients (15/18) were treated with the MOPP/ABV(D) combination chemotherapy followed by mantle field irradiation in 10 patients. Hormonal profile [luteinizing hormone (LH), follicle stimulating hormone (FSH), oestradiol, testosterone, progesterone, insulin-like growth factor (IGF)-1, prolactin] was taken before the GnRHa/chemotherapy co-treatment, and monthly thereafter until resuming spontaneous ovulation and menses. This group of prospectively treated lymphoma patients was compared to a matched control group of 18 women (aged 17-40 years) who have been treated with chemotherapy, mostly MOPP/ABV (14/18), with (11) or without (7) mantle field radiotherapy. Fourteen had Hodgkin's and four non-Hodgkin's lymphoma. Gonadal function was determined clinically, hormonally (LH, FSH, oestradiol, progesterone), and sonographically. Two of the patients in each group died from refractory disease. Of the remaining 16 patients, 15 (93.7%) resumed spontaneous ovulation and menses within 3-8 months of termination of the combined chemotherapy/GnRHa co-treatment. In contrast, only seven (39%) of the 18 similarly treated patients in the control group (chemotherapy without GnRHa) resumed ovarian cyclic activity (regular menses). The other 11 experienced premature ovarian failure (POF) (61%). Out preliminary data suggest a possible significant protective effect of GnRHa co-treatment with chemotherapy from irreversible ovarian damage (POF).