Effects of FSH on serum immunoreactive inhibin levels in the luteal phase of the menstrual cycle.

OBJECTIVE: FSH causes a dose-related increase in circulating immunoreactive inhibin (INH) in the follicular phase of the menstrual cycle, while LH is the major stimulus to INH secretion by the corpus luteum. The present study was undertaken to assess whether FSH can also stimulate INH production during the luteal phase. DESIGN: Normal volunteers were treated with a single injection of LH-free FSH (Metrodin, 150 units) or saline as control, during the early, mid- or late luteal phase of the cycle, with subsequent hormone measurements. PATIENTS: The 21 volunteers were aged 19-29. Seven subjects given FSH and 8 controls were studied in the early luteal phase, 1-4 days post ovulation. Eight FSH treated subjects and 10 controls were studied in the midluteal phase, 5-9 days post ovulation, and 6 each, respectively, were studied in the late luteal phase. MEASUREMENTS: Oestradiol (E2), progesterone (P), and INH were measured by previously described radio-immunoassays. RESULTS: In both the early and mid-luteal phases, FSH caused a significant rise in INH (early, from 778 to 922 U/l, mid-luteal 1553 to 2090 U/l) and E2 (early 371 to 545 pmol/l, mid-luteal 528 to 636) while there was no significant change in P. No significant changes occurred in the saline treated subjects. In the late luteal phase FSH prevented the significant fall in INH seen in the controls, whilst there was no effect on E2 or P. CONCLUSIONS: It was concluded that both FSH and LH are capable of modulating inhibin production during the luteal phase of the menstrual cycle. FSH may exert its actions on the corpus luteum or alternatively on developing follicles. The present study cannot clearly distinguish between these possibilities.

Serum inhibin during lactation: relation to the gonadotrophins and gonadal steroids.

OBJECTIVE: The aims of the study were to describe the changes in serum immunoreactive inhibin (INH) during normal lactation and to examine the relations between INH, oestradiol (E2) and follicle stimulating hormone (FSH), particularly during the first weeks post partum. DESIGN: Blood samples were obtained from normally lactating women for hormone measurements at daily intervals until discharge from hospital, and subsequently at weekly intervals until the resumption of menses, or one year post partum. SUBJECTS: Eighteen breast feeding women aged 27-36 years volunteered for the study. MEASUREMENTS: INH, FSH, luteinizing hormone (LH), prolactin (PRL), E2, and progesterone (P4) were measured by standard radioimmunoassays. Non-linear modelling was used to quantify the hormone patterns observed. RESULTS: Hormone levels were compared with those found in the follicular phase of the normal menstrual cycle. Levels of INH fell rapidly in the first week post partum and remained at the lower end of the follicular phase range for the period of study, rising only just prior to resumption of menses. E2 fell more slowly, into the follicular phase range, reaching the lower end of that range only at about approximately 100 days post partum. FSH levels were suppressed initially below the follicular phase range, commencing to rise 4.7-24 days post partum, reaching a plateau high in the follicular phase range 17.5-53 days post partum, and subsequently showing a slow decline. Human chorionic gonadotrophin (hCG), initially measured because of its cross-reactivity in the LH assay, fell rapidly post partum and LH remained in the low follicular phase range for several weeks. PRL fell slowly throughout and was still elevated at 150 days post partum, while P4 fell very rapidly and was less than 1 nmol/l until just prior to first menses. CONCLUSIONS: Inhibin levels fall rapidly post partum and remain low until close to the time of resumption of follicular activity and menses. The post partum rise in serum FSH appears to be much more closely related to falling oestradiol levels than to the very early and rapid fall in inhibin. Oestradiol thus appears to be the predominant negative feedback factor influencing FSH secretion during the post partum period. The low inhibin levels may allow FSH to rise to levels high in the follicular phase range under the predominant negative feedback control of oestradiol. Inhibin levels do not appear to be a suitable marker of returning fertility.

Perimenopausal patterns of gonadotrophins, immunoreactive inhibin, oestradiol and progesterone.

In order to assess the possible role of circulating immunoreactive inhibin (INH) during the menopausal transition, two groups of subjects were studied. Four were normal volunteers, three of whom had developed their first symptoms of cycle irregularity at age 45-46 years, the fourth being aged 37, a volunteer for a study involving daily blood sampling found to have a transient rise in serum follicle stimulating hormone (FSH). Six were patients with anovulatory infertility, aged 34-44 years, found to have transitory ovarian failure during attempts at ovulation induction. Intermittent blood samples were obtained for radioimmunoassay of serum FSH, luteinizing hormone (LH), INH, oestradiol (E2), and progesterone. Abrupt changes were observed, with transient elevations of FSH and LH and decreases of INH and E2 into the postmenopausal range, followed by levels more characteristic of reproductive-aged women. It was concluded that typical postmenopausal hormone patterns may occur at the time of entry into the normal menopausal transition, and in some women with anovulatory infertility, but may be completely and relatively abruptly reversible. Elevation of serum FSH into the postmenopausal range, with undetectable INH concentrations, does not provide reliable evidence that the menopause (or permanent ovarian failure) has occurred. INH contributes to elevations of serum FSH during the menopausal transition.

Clinical and pathophysiological aspects of inhibin.

Inhibin is a peptide hormone normally produced by the ovary. We have previously reported that serum inhibin concentrations are elevated in patients with granulosa cell tumours of the ovary. The aim of this study was to measure serum inhibin in a prospective, consecutive series of 200 patients admitted for suspected ovarian cancer. The serum inhibin radioimmunoassay had a sensitivity of 77 mu/l. The median effective dose was 640 mu/l, while within- and between-assay coefficients of variation in the region of maximal assay precision were 4.3% and 4.3%, respectively. The average effective doses (10 and 90%) in 35 consecutive assays were 211 and 1908 mu/l, respectively. We designated a serum inhibin concentration of > or = 130 mu/l as pathological in castrate or functionally agonadal women. Serum inhibin concentrations were elevated in 12 of 13 post-menopausal patients with mucinous cystadenocarcinoma of the ovary. By contrast, elevated serum inhibin values were found in only nine of 65 women with non-mucinous epithelial ovarian cancers. All patients showed a fall in serum inhibin levels to below 130 mu/l by 1 week after surgery. In post-menopausal women (n = 54) with proven ovarian cancer, serum inhibin concentrations correlated negatively with serum FSH and the clinical stage of their disease (P < 0.05). By contrast, serum inhibin correlated positively with serum oestradiol and progesterone (P < 0.001) but there was no correlation between serum inhibition and serum CA-125 values. We conclude that serum inhibin concentrations are typically elevated in patients proven to have mucinous cystadenocarcinoma of the ovary.(ABSTRACT TRUNCATED AT 250 WORDS)

Elevated serum inhibin concentrations in postmenopausal women with ovarian tumors.

BACKGROUND: Inhibin is an ovarian hormone that inhibits the secretion of follicle-stimulating hormone (FSH) by the anterior pituitary gland. Women with granulosa-cell tumors of the ovary have elevated serum inhibin concentrations, but whether the concentrations are increased in women with other ovarian tumors is unknown. METHODS: We measured serum inhibin and FSH concentrations before surgery in 212 postmenopausal women with suspected ovarian cancer and after surgery in 210 of them. RESULTS: Eighteen of the 22 women (82 percent) with mucinous carcinomas (mucinous cystadenocarcinomas and mucinous borderline cystic tumors) of the ovary had elevated serum inhibin concentrations, whereas only 9 of the 53 women (17 percent) with serous carcinomas (serous cystadenocarcinomas and serous borderline cystic tumors) had elevated levels. Serum inhibin concentrations were also elevated in 2 of 12 women (17 percent) with clear-cell carcinomas, 4 of 26 women (15 percent) with undifferentiated carcinomas, 3 of 3 women (100 percent) with granulosa-cell tumors, and 5 of 27 women (19 percent) with other ovarian cancers. The serum concentrations of inhibin were increased in 2 of 28 women (7 percent) with nonovarian pelvic cancers and 11 of 41 women (27 percent) with benign ovarian diseases. All women but one with initially elevated serum inhibin concentrations had low values one week after surgery. Serum inhibin concentrations correlated negatively with serum FSH concentrations (P = 0.05) in women with granulosa-cell tumors but not in women with other tumors, suggesting that the inhibin secreted by tumors in the latter group has decreased biologic activity. CONCLUSIONS: Serum inhibin concentrations are elevated in most postmenopausal women with mucinous carcinomas of the ovary and in some women with other types of epithelial ovarian tumors. The concentrations fall after tumor removal.

Follicle-stimulating hormone induces dose-dependant stimulation of immunoreactive inhibin secretion during the follicular phase of the human menstrual cycle.

To determine whether FSH is a physiological regulator of the serum immunoreactive inhibin (INH) concentration during the follicular phase of the normal menstrual cycle, purified FSH (Metrodin) was administered in doses of 100 IU (n = 6), 150 IU (n = 5), and 200 IU (n = 5) to normal, regularly cycling volunteers between days 3-7 of the menstrual cycle. A control group (n = 5) received normal saline. There was a linear dose-related increase in serum INH (and in serum FSH) in response to the three doses of FSH, with 200 IU leading to a 107% increase in INH and a 68% increase in FSH. Serum estradiol rose in response to the two higher doses of FSH. There was a significant correlation between the actual increases in INH and estradiol (r = 0.53; P < 0.01). It was concluded that FSH stimulates INH in the follicular phase of the normal menstrual cycle, consistent with a physiological role for FSH in the regulation of granulosa cell production of inhibin.

GnRH agonist analog therapy in advanced/recurrent granulosa cell tumors: further evidence of a role of inhibin in monitoring response to treatment.

Five patients with advanced ovarian granulosa cell malignancies resistant to cytotoxic chemotherapy were treated with monthly subcutaneous injections of long-acting gonadotropin releasing hormone (GnRH) agonist analog. One partial response and one stabilization of the disease were observed. In three patients, the tumor continued to progress. Treatment response was monitored with serum inhibin assay. Four patients had high serum inhibin concentrations at the beginning of GnRH analog treatment, while one patient had an inhibin-negative tumor. In three of four patients, serum inhibin remained relatively constant, or decreased during the first 3 months of therapy. It subsequently increased, in parallel with clinical deterioration. Further clinical trials with GnRH analogs are warranted in this malignancy in which serum inhibin appeared to be a clinically valuable tumor marker.

Vaginal progesterone administration in physiological doses normalizes raised luteinizing hormone levels in patients with polycystic ovarian syndrome.

A raised luteinizing hormone (LH) level is a typical finding in the polycystic ovarian syndrome (PCOS). This inappropriate elevation of LH is thought to interfere with normal follicular development and ovulation. The resulting chronic anovulation is associated with the absence of the luteal phase increase in secretion of progesterone and inhibin. Progesterone can exert both a positive and negative feedback action on LH secretion, but inhibition is thought to occur following prolonged exposure to progesterone. Therefore, the aim of this study was to see if exogenously administered progesterone in physiological doses would normalize circulating LH concentrations in patients with PCOS. Vaginal progesterone was administered twice daily in a dose of 100 mg, at 12 h intervals, to ten women with PCOS. Serum samples were taken on alternate days for radioimmunoassay of follicle stimulating hormone (FSH), LH, estradiol, progesterone and inhibin. To determine the effect of progesterone on LH secretory dynamics in PCOS, LH pulse studies were carried out prior to treatment, and on day 10 of progesterone administration in four of the ten subjects. Mean serum progesterone concentrations reached 51 nmol/l by 4 days after exogenous progesterone treatment, and remained in the mid-luteal phase range, as established in 12 normal cycles, during the use of the vaginal suppository. The mean serum LH concentration had fallen significantly (p < or = 0.01) after 8 days of treatment, and continued to fall progressively until the end of progesterone administration. Serum LH concentrations had fallen into the normal follicular phase range by 14 days (mean 5.5, range 3.4-10.9 IU/l; normal follicular phase range 1.8-10.0 IU/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Circulating immunoreactive inhibin and testosterone levels in men with critical illness.

OBJECTIVE: We aimed to concurrently characterize serial changes in circulating immunoreactive inhibin (irINH) and testosterone (T) as reflections of Sertoli and Leydig cell responses to acute critical illness in man. DESIGN: Blood samples were drawn within 24 hours of admission to an Intensive Care Unit and at weekly intervals thereafter for up to 4 weeks while the patient remained in Intensive Care Unit or after discharge to a general ward. PATIENTS: We studied 13 male subjects with critical illness requiring intensive therapy. MEASUREMENTS: Plasma levels of irINH, T, LH, FSH and sex hormone binding globulin (SHBG) were analysed in relation to (i) the severity of illness as indicated by a sepsis score, acute physiology and chronic health evaluation score, and reverse triiodothyronine (rT3) levels and (ii) the outcome of illness as determined by discharge from Intensive Care Unit and the two-month mortality. RESULTS: Overall irINH levels remained normal and correlated negatively with rT3 (r = -0.63, P = 0.001) but not with sepsis, acute physiology and chronic health evaluation score, or gonadotrophin levels. Neither admission nor serial irINH levels significantly distinguished between the different clinical outcomes. In contrast, T levels were depressed and inversely correlated with both sepsis and acute physiology and chronic health evaluation scores (P less than 0.02), and positively with gonadotrophins (P less than 0.01), but not rT3 levels. Men eventually discharged from the Intensive Care Unit showed a rise, while those remaining showed a fall, in T levels (P = 0.02, time-course interaction). Similarly, T levels were lower in patients who died than in survivors, despite the comparable T levels on admission (P = 0.02, time-course interaction). Despite the fall in T levels, gonadotrophin levels remained inappropriately in the eugonadal range but higher in men who were discharged from Intensive Care Unit (P = 0.02, time-course interaction). FSH but not LH levels were correlated with sepsis score (P = 0.02) but not acute physiology and chronic health evaluation score or rT3. CONCLUSIONS: Sertoli cell function as judged by circulating irINH levels is much less affected by acute critical illness than is Leydig cell function as judged by circulating T levels. The suppressive effect of acute critical illness on Leydig cell function is consistent with a hypothalamic-pituitary lesion.

Inhibin as a marker for granulosa cell tumor.

In order to determine whether serum-immunoreactive inhibin could constitute a biochemical marker for the presence and progression of ovarian granulosa cell tumors and their metastases, we measured immunoreactive inhibin concentrations in series of serum samples obtained from 8 patients with granulosa cell tumor. Six series were tested in retrospect. From these, three came from patients who had been treated with an abdominal hysterectomy and bilateral salpingo-oophorectomy. In the 2 patients with residual or recurrent disease, inhibin was elevated, 4 and 20 months respectively before clinical manifestations of recurrence became evident; it reflected the effects of secondary therapy. Inhibin remained undetectable in one patient who was free of disease during 11 years of follow-up. Inhibin concentrations were also inappropriately increased in 2 of 3 women with amenorrhea and infertility resulting from small granulosa cell tumors. After removal, inhibin concentrations became normal and fertility resumed. Fertility also returned in the third patient. There was a significant negative correlation between the serum inhibin and FSH concentrations, consistent with autonomous production of inhibin by granulosa cell tumors. It is concluded that granulosa cell tumors have the capacity to produce inhibin. In retrospect, inhibin proved to be a marker for both primary and also recurrent and residual disease.

Control of inhibin production by dispersed human luteal cells in vitro.

The production of inhibin in vitro by dispersed cells from early to mid (Days 16-19) and late stage (Day 23) human corpus luteum (CL) was examined, and the effects of human chorionic gonadotrophin (hCG), follicle stimulating hormone (FSH), oestradiol and testosterone on inhibin production were determined. Corpora lutea from five subjects in the early to mid luteal stage and three subjects in late luteal stage were dispersed with enzymes and the luteal cells cultured in medium supplemented with 5% calf serum and either FSH (1, 10 or 100 ng mL-1), oestradiol-17 beta (2.5, 5 or 10 micrograms mL-1) or testosterone (0.25, 1 or 5 micrograms mL-1) with or without hCG (1 I.U. mL-1). Cells were cultured for 1 to 3 days without changes of medium, and the concentrations of progesterone, oestradiol and immunoreactive inhibin in the medium were measured by radioimmunoassay. Cells from both types of CL produced inhibin in vitro under basal conditions, but only cells from early to mid CLs responded to hCG with a significant increase in inhibin production. Both progesterone and oestradiol production were stimulated by hCG in both groups of CL. Inhibin concentrations in the cell cultures declined with time in culture, particularly in the late CL group, whereas the concentration of steroids increased. Neither FSH, oestradiol nor testosterone significantly changed inhibin production in either CL group. It was concluded that inhibin production by human luteal cells in vitro is influenced by the age of the CL, and is dependent on LH (hCG) but not on FSH or sex steroids.

Inhibin and age in men.

OBJECTIVE: Normal elderly men are reported to have decreased testicular function despite elevated gonadotrophin levels. We wished therefore to determine if changes in testicular function occur over the age range 19-60 years. DESIGN: Single fasting blood samples were obtained between 0800 and 0900 h. PATIENTS: Working men in a large industrial company between the ages of 19 and 60 years participated in the study. MEASUREMENTS: FSH, serum immunoreactive inhibin and total testosterone were measured, the latter two as measurements of Sertoli and Leydig cell function respectively. RESULTS: The mean baseline serum immunoreactive inhibin level was significantly lower in men from the older age groups, 31-40 years (479 U/l), 41-50 years (439 U/l) and 51-60 years (415 U/l) than in men from the youngest age group, 21-30 years (613 U/l) while serum FSH was higher in men from the older age groups, 41-50 years (3.7 IU/l) and 51-60 years (6.1 IU/l) than in men from the youngest age group, 21-30 years (2.6 IU/l). There appears to be a change in both FSH and inhibin production, consistent with a primary decline in testicular function. There was no significant difference in testosterone levels between the older age group, age 51-60 years and the younger age group, age 21-30 years. However, testosterone levels were significantly lower in the 41-50 year age group, when compared with the 21-30 year, this significance levelling out at about age 45 years. CONCLUSION: The data are consistent with the hypothesis that immunoreactive inhibin reflects inhibin bioactivity, and that inhibin plays a role in the feedback control of FSH secretion in men.

Follicular arrest during the midfollicular phase of the menstrual cycle: a gonadotropin-releasing hormone antagonist imposed follicular-follicular transition.

The functional dependency of the dominant follicle on pulsatile gonadotropin inputs was evaluated by using a GnRH antagonist as a probe. Hormonal dynamics, particularly the relationship of FSH, estradiol, and inhibin, during and after the withdrawal of GnRH receptor blockade achieved by treatment with Nal-Glu GnRH antagonist (50 micrograms/kg, im) for 3 days in the midfollicular phase of the cycle (days 7-9) were ascertained. Daily blood samples were obtained for LH, FSH, estradiol (E2), progesterone, and immunoreactive inhibin (i-INH) measurements by RIA during 2 consecutive (control and treatment) cycles in 12 women. In 5 women, LH pulsatility was assessed by 10-min blood sampling for 12 h before, during, and after Nal-Glu treatment. The administration of Nal-Glu prolonged both follicular phase (14.0 +/- 0.5 vs. 19.7 +/- 0.8 days; P less than 0.0001) and total cycle length (28.1 +/- 0.5 vs. 34.1 +/- 1.2 days; P less than 0.0001). Gonadotropin suppression (50-60%) was achieved, as reflected by a marked decrease in mean LH levels (14.3 +/- 1.9 to 5.4 +/- 0.5; P less than 0.01) and LH pulse amplitude (5.5 +/- 0.7 to 2.4 +/- 0.3 IU/L; P less than 0.01) in response to Nal-Glu antagonist. The number of LH pulses was reduced (36%), but pulses remained discernible. Concentrations of FSH (10.8 +/- 1.4 to 5.9 +/- 0.4 IU/L; P less than 0.05), E2 (322.7 +/- 71.9 to 84.8 +/- 7.7 pmol/L; P less than 0.01) and i-INH (284.0 +/- 25.9 to 164.4 +/- 7.5 U/L; P less than 0.01) decreased concomitantly. Within 24-48 h of the last injection of Nal-Glu, all hormones had returned to pretreatment levels. This was followed by normal functional expression of follicular growth and maturation, as reflected by an increase in E2 and i-INH levels, timely ovulation, and normal luteal function. These findings indicate that an approximately 50% decline in gonadotropin support to the dominant follicle leads to functional arrest, but not demise, of the developing follicle(s) without triggering new folliculogenesis. The follicular apparatus retained its ability to reinitiate its original functionality once appropriate gonadotropin inputs were reinstated.

Serum gonadotropin, sex steroid, and immunoreactive inhibin levels in the first two years of life.

To characterize the changes in serum immunoreactive inhibin (INH) in the first 2 yr of life, blood samples were obtained from 46 boys (age range, 61-659 days) and 37 girls (76-666 days) undergoing minor surgery for nonendocrine related conditions. Serum levels were compared with those of simultaneously measured FSH, LH, and either testosterone (T) or estradiol (E2). In the boys, the levels of all 4 hormones fell progressively with age up to about 300 days, with a minor fall only in the second year. FSH (0.7-1.4 IU/L) was initially at the lower adult male limit, while LH (3.2-5.0 IU/L) was at the midrange. T levels (2.2-3.3 nmol/L) were in the adult female range, while INH (200-820 U/L) was in the midrange for men. In the youngest girls, FSH levels (12-26 IU/L) were frequently above the upper limit of normal for the adult follicular phase, but fell to approximately 2.0 IU/L after 300 days. LH levels (0.5-3.5 IU/L) were at the lower adult normal limit and changed little with age, while E2 levels in the youngest girls (280-550 pmol/L) were in the midfollicular range, but were generally less than 10 pM at more than 200 days. INH levels (175-260 U/L) were in the low adult range initially, but the majority were undetectable over 200 days. In the boys, significant negative correlations were observed for all 4 hormones with age, while FSH, LH, and T were positively correlated with INH. In the girls, there were weaker negative correlations of the 4 hormones with age, but no significant correlations between the gonadotropins and INH. E2 was strongly correlated with INH. Thus, the previously described early postnatal activation of the hypothalamo-pituitary-gonadal axis involves INH as well as the se steroids and gonadotropins. FSH levels in young girls were strikingly high, and INH levels were much higher in boys than girls. The low INH levels in girls may contribute to the elevated FSH seen during the period of neonatal gonadal activation.

Circulating levels of inhibin in pregnant women at term: simultaneous disappearance with oestradiol and progesterone after delivery.

Circulating levels of immunoreactive inhibin (ir-inhibin) and its disappearance after delivery of the placenta were determined in seven pregnant women at term. Serum oestradiol (E2) and progesterone (P4) levels were measured simultaneously and served as comparisons. Fetal contributions of ir-inhibin were assessed by determining concentrations in the umbilical artery (UA) and vein (UV). Relative changes in circulating levels of ir-inhibin, E2, and P4 were compared to levels found in nonpregnant women during the early follicular phase (EFP) and mid-luteal phase (MLP) of the normal menstrual cycle. In pregnant women, ir-inhibin levels at delivery were 15- and 3-fold higher than EFP and MLP values respectively. The disappearance of all three hormones after removal of the placenta followed a bi-exponential curve with an initial, rapid component and a second, slower component. There was a highly significant positive correlation between the disappearance curves of all three placental hormones (r = 0.97, P less than 0.0001). Concentrations of ir-inhibin in the cord blood were about half that in maternal serum and without significant difference between levels in UA and UV.

Treatment of anovulation due to polycystic ovarian syndrome by laparoscopic ovarian electrocautery.

Our experience of ovarian electrocautery for the treatment of polycystic ovarian syndrome (PCOS) in ten women is described. We found that nine responded favourably, either ovulating spontaneously or becoming more responsive to ovulation induction. There was a significant and persistent fall in serum testosterone levels, and a transient fall with subsequent rise in inhibin. We recommend that laparoscopic ovarian electrocautery is considered as an alternative to ovulation induction with gonadotrophins, in women with PCOS who fail to respond to clomiphene citrate.

Human chorionic gonadotrophin raises serum immunoreactive inhibin levels in men with hypogonadotrophic hypogonadism.

Inhibin is a gonadal glycoprotein hormone involved in the regulation of FSH. To elucidate the regulation of inhibin production we investigated the acute (daily for 1 week) and chronic (9-10 months of follow-up) changes in immunoreactive inhibin, testosterone, LH and FSH levels in the serum of three hypogonadotrophic hypogonadal patients treated first with hCG alone (for 3-6 months) and then hCG combined with FSH (1-5 months). One patient was unexpectedly resistant to gonadotrophin therapy; in the other two, hCG, with or without FSH, caused a rise in inhibin and testosterone, supporting previous observations that LH, as well as FSH, plays a role in the regulation of inhibin or inhibin-related peptides in men.

Dynamic changes in circulating inhibin levels during the luteal-follicular transition of the human menstrual cycle.

Dynamic changes in serum immunoreactive (ir) inhibin levels during the transition from the luteal to the follicular phase (luteal-follicular transition) were characterized during 3 consecutive cycles in 12 cycling women. Both spontaneous (first to second cycle) and GnRH antagonist-imposed premature luteolysis (second to third cycle) were evaluated. Serum FSH, LH, estradiol (E2), and progesterone (P4) levels were monitored daily by RIA for the entire study. Daily ir-inhibit levels were determined from 7 days before until 7 days after the onset of menses and from 4 days before to 10 days after the GnRH antagonist-induced bleeding by a heterologous RIA. During spontaneous luteolysis, ir-inhibin levels peaked 7 days before menses and declined in a linear fashion (r = -0.99) thereafter, reaching a sustained low level 1 day after the onset of menses. The decline of P4 and E2 levels appears to be coupled to that of ir-inhibin (r = 0.98 and r = 0.95, respectively). FSH levels showed an inverse pattern, with an acute elevation unaccompanied by LH, for 5 days before the onset of menses and reaching a plateau 2 days after. ir-Inhibin and FSH were negatively correlated (r = -0.87; P less than 0.0001). Increased LH levels did not occur until the day of menses and were negatively correlated with ir-inhibin (r = -0.50; P less than 0.05), but not E2 and P4. During the second cycle, at the midluteal phase luteolysis was induced by a single (50 micrograms/kg) im injection of a potent GnRH antagonist, [Ac-D2Nal,D4ClPhe2,D3Pal3,Arg5,DGlu6(AA),+ ++DAla10] GnRH; an acute decline of LH and FSH levels occurred, with maximal suppressions of 51% and 35%, respectively. ir-Inhibin levels decreased rapidly (40 +/- 2.8%) in parallel with E2 and P4 during the first 24 h and continued to decline for 4 days. The inverse relationship and time course of changes between FSH and ir-inhibin levels were similar to those of the spontaneous luteal-follicular transition. Six of the 12 subjects experienced partial reversal of luteolysis; the decline of ir-inhibin and the rise of FSH during the first 2 days were arrested for 4 days, which corresponded to the rebound increases in E2, P4, and LH. The subsequent fall of ir-inhibin was followed by a rise in FSH. Both the complete and incomplete luteolysis groups exhibited an orderly follicular maturation, LH surge, and luteal function during the ensuing cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

Inhibin as a marker for granulosa-cell tumors.

Inhibin is a peptide hormone normally produced by ovarian granulosa cells. It reaches a peak of 772 +/- 38 U per liter in the follicular phase of the menstrual cycle and is undetectable in the serum of menopausal women. To determine whether measurements of serum inhibin levels would provide a biochemical marker of the presence or progression of ovarian granulosa-cell tumors and their metastases, we measured the serum immunoreactive inhibin concentrations in six women with such tumors. Three women had been treated by hysterectomy and bilateral salpingo-oophorectomy. In the two women with residual or recurrent disease, the serum inhibin levels were abnormally elevated 5 and 20 months before the clinical manifestations of recurrence became evident. The maximal concentrations approached 3000 U per liter. The serum inhibin level remained undetectable in one patient who was disease-free for 11 years. Serum inhibin concentrations were also elevated in three women with amenorrhea and infertility that resulted from small granulosa-cell tumors. After the removal of the tumors, the serum inhibin levels in these women became normal, and fertility returned. There was a significant negative correlation between the serum concentrations of inhibin and follicle-stimulating hormone, in a manner consistent with the autonomous production of inhibin by granulosa-cell tumors. We conclude that granulosa-cell tumors produce inhibin. Since serum inhibin levels reflect the size of the tumor, measurements of inhibin can be used as a marker for primary as well as recurrent disease.

Serum inhibin concentrations rise throughout normal male and female puberty.

Using a newly developed, sensitive, and specific RIA, we measured the serum concentrations of inhibin, together with those of FSH, LH, and sex steroids, throughout puberty in 99 boys and 102 girls attending a suburban Melbourne school. Serum inhibin levels rose from a geometric mean level of 161 U/L (range, 87-310; 67% confidence interval) at stage I puberty in boys to 442 U/L (range, 300-626) at stage V, while corresponding values in girls were 97 U/L (range, 46-204) and 231 U/L (range, 187-372), respectively. Serum inhibin concentrations were strongly correlated with age and serum FSH, LH, testosterone, and estradiol; all hormones increased in parallel in both boys and girls. After adjustment for age, the partial correlation coefficients remained significant only for testosterone in the boys. We hypothesize that gonadal inhibin production is stimulated by rising gonadotropin levels during pubertal development.