Pituitary dysfunction in recently post-menopausal women.
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Female↗
Biomedical subjects
H G Burger
Publications and source records attributed to H G Burger.
No evidence of a role for mutations or polymorphisms of the follicle-stimulating hormone receptor in ovarian granulosa cell tumors.
The molecular pathogenesis of granulosa cell tumors of the ovary is not understood, although recent studies have shown that immunoreactive inhibin secretion by these tumors may be used as a tumor marker. Granulosa cell tumors exhibit many features of normal granulosa cells, including a response to FSH and inhibin secretion. FSH levels are suppressed in patients with inhibin-secreting granulosa cell tumors, suggesting FSH-independent growth of these tumors. Activating mutations of the FSH receptor might, therefore, be involved in tumorigenesis. We sought to identify mutations in the FSH receptor genes of these tumors using PCR to amplify the exon encoding the transmembrane and cytoplasmic domains from the tumor DNA. Analysis of the amplicons for single strand conformational polymorphisms and direct sequencing confirmed a previously reported polymorphism in the C-terminal region of the receptor, but did not identify tumor-specific missense mutations and/or polymorphisms. In addition, ribonucleic acid from 3 granulosa cell tumors was used to confirm expression of the FSH receptor; expression was unexpectedly also observed in several ovarian mucinous cystadenocarcinomas used as controls. In conclusion, our failure to identify activating mutations of the FSH receptor in 15 granulosa cell tumors argues against a role for the FSH receptor in tumorigenesis and suggests that some subsequent component of this signal transduction pathway may be activated.
Alleles↗
Both inhibin A and B respond to exogenous follicle-stimulating hormone in the follicular phase of the human menstrual cycle.
To ascertain whether changes in the concentrations of the dimeric inhibins A and/or B (INH-A and INH-B) contributed to the previously described dose-dependent increase in immunoreactive inhibin (INH) in response to FSH during the follicular phase of the human menstrual cycle, both dimers were measured by specific two-site assays in stored serum samples from regularly cycling normal volunteers who had received saline as a control (n = 5) or FSH [100 IU (n = 6) or 200 IU (n = 5)] between days 3-5 of the menstrual cycle. Both INH-A and INH-B showed a dose-dependent increase in response to administered FSH; INH-A rose from 13.5 to 35.9 ng/L (P < 0.01), and INH-B rose from 77.8 to 205 ng/L (P < 0.05) at 36 h after 200 IU FSH. Highly significant correlations were observed between INH and each of the specific inhibin dimers (A: r = 0.79, P < 0.001; B: r = 0.76, P < 0.001), and the responses of the two dimers were also highly correlated (r = 0.59, P < 0.001). The response of each inhibin was also highly correlated with the response of serum estradiol (A: r = 0.45, P < 0.001; B: r = 0.40, P < 0.001). When analyzed by ANOVA, the INH response of INH-B was significantly above the control value at 36 h after treatment with both 100 and 200 IU FSH, whereas the response of INH-A was significant only at 200 IU. It is concluded that the concentrations of both dimeric INH-A and INH-B are stimulated by increases in FSH within the physiological range in the follicular phase of the human menstrual cycle and that both contribute to the previously observed rise in INH.
Adult↗
Using longitudinal data to define the perimenopause by menstrual cycle characteristics.
OBJECTIVES: To determine which aspects of menstrual change best predict time to postmenopause. METHODS: A total of 250 Australian-born women aged 45-55 years were divided into five menstrual status categories: Group I reported no change in menstrual flow or frequency; Group II reported change in flow; Group III reported change in frequency; Group IV reported change in both frequency and flow; and Group V reported between 3 and 11 months of amenorrhea. Menstrual status groups were compared on baseline data for age, hormone levels, hot flushes and self-rated menopausal status. The proportion of women moving to postmenopause in subsequent years was compared using 4 years of follow-up data. RESULTS: Women in Group V were older, had lower estradiol and inhibin levels, higher follicle stimulating hormone levels, and were more likely to report hot flushes, and to self-rate themselves as having started the menopausal transition, compared with the women who had menstruated in the last 3 months (Groups I-IV). Groups I and II were similar in age and hormonal status, as were Groups III and IV. The proportion of women who had moved to postmenopausal status in the 4 years after baseline were 12%, 14%, 58%, 53% and 94% for Groups I-V, respectively. CONCLUSIONS: Amenorrhea is the best predictor of future menopause followed by changes in menstrual frequency. Change in flow only was not predictive of future menopause. A two-stage classification scheme is suggested for defining the perimenopause. 'Early perimenopause' is defined as the self-reporting of changes in menstrual frequency over the last year, and 'late perimenopause' is defined as the self-report of 3-11 months of amenorrhea.
Amenorrhea↗
The Y chromosome and spermatogenesis.
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Chromosome Deletion↗
Editorial: inhibin in the male--progress at last.
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Animals↗
The biological and immunological characterization of inhibin A and B forms in human follicular fluid and plasma.
In a previous study (see Ref.7), the molecular weight distribution of inhibin activity in fractionated human follicular fluid (hFF) and human male and female plasma/serum was determined by in vitro bioassay using ovine pituitary cells in culture and various specific inhibin A and inhibin alpha-subunit-directed immunoassays. It was shown, however, that the ovine in vitro bioassay detected inhibin B poorly. These findings are extended in the present study by the determination of the molecular weight profile of in vitro bioactivity using rat pituitary cells, which detects both inhibin A and B, a specific inhibin B enzyme-linked immunosorbent assay (ELISA), an RIA detecting the alpha N region of the alpha-subunit, an alpha-subunit ELISA (Pro-alpha C) directed to the inhibin forms containing the Pro sequence, and an alpha C subunit immunofluorometric assay that detects all inhibin forms. The profile in hFF of inhibin in vitro bioactivity, using rat pituitary cells in culture, significantly (P < 0.001) correlated with in vitro bioactivity using ovine pituitary cells (r = 0.85), inhibin A immunoactivity (r = 0.70), inhibin B immunoactivity (r = 0.89), and the combination of inhibin A + B immunoactivities (r = 0.93), with peaks of activity identified at 66K, 55K, 36K and 33K, consistent with presumed known mol wt forms of inhibin. Inhibin B profiles in fractionated serum from women stimulated with gonadotropins and male plasma consisted of two forms (66K and 36K), whereas inhibin A in female serum included, in addition, the 55K form. These findings indicated that higher molecular weight forms of inhibin B are present in biological samples, and their distribution differs from that of inhibin A, suggesting a differential processing of the precursor forms in the circulation. Pro-alpha C immunoactivity was identified in serum samples with prominent peaks at 36K and 29K (known Pro-alpha C subunit forms) and not with any high mol wt dimeric forms of inhibin. If this observation applies to a wider range of serum samples, the Pro-alpha C ELISA may provide an appropriate and specific assay for the measurement of free alpha-subunit. To compare immunoactivity levels between assays, the inhibins A, B, and Pro-alpha C standards were calibrated in terms of their alpha C subunit content, as determined by an alpha C subunit immunoassay, with the inhibin B standard containing 60% of the alpha C subunit content compared with either the inhibin A or Pro-alpha C standard. After adjustments of the various standards for this difference in alpha C subunit content, a comparison was undertaken of the combined levels of inhibins A, B, and Pro-alpha C immunoactivity across the hFF and serum chromatograms and compared with levels determined by the alpha-subunit-directed immunoassays. A high correlation (r = 0.59-0.96) was observed, indicating that the alpha-subunit immunoactivity in serum consists largely of a composite of presumed known molecular weight forms of inhibins A, B, and Pro-alpha C. It is concluded that: 1) inhibin in vitro bioactivity in hFF is largely attributed to the presence of 33-36K and 50-66K forms of inhibins A and B; and 2) inhibin alpha-subunit immunoactivity in hFF and serum is a composite of presumed known forms of inhibin A, inhibin B, and the alpha-subunit.
Animals↗
Use of androgens in postmenopausal women.
Serum androgen levels decline with age in women, a decline already demonstrable prior to menopause. Oestrogen administration is associated with a decrease in bioavailable testosterone. Testosterone administration can lead to increases in a number of parameters of sexuality, probably by direct neural effects. Androgens also have anabolic effects on bone, and do not adversely affect lipids, especially when given parenterally.
Animals↗
Screening for osteoporosis: what is the role of heel ultrasound?
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Absorptiometry, Photon↗
Hot flushes, menstrual status, and hormone levels in a population-based sample of midlife women.
OBJECTIVE: To determine the frequency of hot flushes in a population sample of 453 pre-, peri-, and postmenopausal women (aged 48-59 years), and to investigate the relationship of hot-flush reporting with menstrual status, serum levels of estradiol (E2), inhibin, and FSH, history of premenstrual complaints, and physical and life-style factors. METHODS: We used a population-based sample. Interviews were conducted in the women's homes. RESULTS: Frequency of hot-flush reporting was associated with menstrual status (P < .001). Twenty-nine percent of women who had more than 3 and less than 12 months of amenorrhea, and 37% of postmenopausal women experienced hot flushes several times a day. In total, 13% of premenopausal women, 37% of perimenopausal women, 62% of postmenopausal women, and 15% of women on hormone therapy reported having had at least one hot flush in the previous 2 weeks. Follicle-stimulating hormone levels were higher in women who experienced hot flushes at least once a day or more (P < .001); E2 levels were higher in women experiencing one or no hot flushes per week (P < .001). The women in the perimenopausal group who experienced hot flushes had higher FSH levels (P = .008) and were more likely to have reported premenstrual complaints at the first interview 3 years earlier (P = .03). In the postmenopausal group, there was no significant difference with any of the variables studied between the women who were experiencing hot flushes and those who were not. CONCLUSION: Reporting of hot flushes is greatest 3 months or more after the final menstrual period. The frequency of hot flushes is associated with increasing FSH, decreasing E2, and a history of premenstrual complaints.
Body Mass Index↗
The endocrinology of the menopause.
Changes in the endocrinology of the pituitary-ovarian axis first become manifest at about the age of 40, a selective rise in serum follicle stimulating hormone (FSH) levels occurring at about the same time as a marked acceleration in the loss of primordial follicles from the ovary. FSH levels gradually increase with increasing age in women who continue to cycle regularly. During the menopausal transition, initiated when changes in cycle frequency or in menstrual flow are first observed, both gonadotrophins, oestradiol and inhibin show a marked degree of variability with abrupt changes from typical post-menopausal patterns to those characteristic of the reproductive age group. Within 1-2 years after the final menstrual period or menopause, FSH levels are markedly elevated, luteinizing hormone (LH) levels moderately so, while oestradiol and inhibin levels are low or undetectable. Post-menopausally, adrenal androstenedione is the major source of oestrogen and serum testosterone levels fall moderately, with oophorectomy leading to a further significant fall. Serum sex hormone binding globulin levels fall to a small degree post-menopausally. Areas of persisting controversy include the question of whether oestradiol levels fall with increasing age prior to the onset of the menopausal transition, the relative roles of oestradiol and inhibin in the selective rise of serum FSH and the role of serum androgens post-menopausally.
Adolescent↗
The menopausal transition.
The menopausal transition is that period beginning with the first indications of the approach of menopause and ending with the final menses. Its morphological basis is a rapidly declining number of primordial follicles within the ovary; a decline which appears to result from an increased rate of follicular atresia. The most characteristic hormonal change in the menopausal transition is a progressive, though often fluctuating, rise in the level of serum FSH. Oestradiol and inhibin levels fluctuate markedly when observed in individual subjects but remain relatively preserved during the follicular phase of the cycle, until late in the menopausal transition. The frequency of anovulatory cycles increases as the final menstrual period approaches. The rate of symptom reporting varies among different populations of women, with maximum symptom frequency being seen during the menopausal transition. There are some indications that cardiovascular and osteoporosis risk factors may change adversely during the menopausal transition and medical practitioners should be ready to offer hormonal supplementation to women at increased risk of cardiovascular disease and osteoporotic fracture.
Adult↗
Characterization of inhibin immunoreactivity in post-menopausal women with ovarian tumours.
BACKGROUND AND OBJECTIVE: We have previously reported elevated serum immunoreactive inhibin (INH) levels in patients with ovarian malignancies, particularly granulosa cell and mucinous tumours. The present study was designed to compare INH measurements using a heterologous radioimmunoassay with cross-reactivity for inhibin alpha-subunit derived peptides with measurements obtained using a new ELISA specific for dimeric inhibin-A. It was hypothesized that granulosa cell tumours may secrete significant quantities of inhibin-A whereas mucinous tumours were unlikely to do so because of the lack of a relation between INH and FSH measurements in the latter group. DESIGN: Serum samples obtained from women found to have ovarian cancer were assayed using the heterologous radioimmunoassay (the Monash assay) and using an ELISA specific for dimeric inhibin (the Groome assay) and the results were compared. PATIENTS: Samples for assay were available from 69 normal post-menopausal control women, 12 patients with mucinous tumours of the ovary, 26 with serous tumours, 7 with granulosa cell tumours and 8 with various other ovarian tumours. Patients were post-menopausal or had been subjected to bilateral oophorectomy at the time these samples were collected. MEASUREMENTS: The Monash and Groome assays were carried out as described previously. The upper limit of normal for post-menopausal women in the Monash assay was 122 U/l and for the Groome assay was calculated to be 32 ng/l. RESULTS: Among the 69 normal subjects, 4 were found to have elevated inhibin levels using the Monash RIA (133-190 U/l) and 4 were found to have elevated levels in the Groome ELISA (45.5-55.3 ng/l). Among 12 patients with mucinous tumours, 10 (83%) had elevated inhibin levels using the Monash assay but only 3 (25%) had elevated levels with the Groome assay (P < 0.005). Among 26 with serous tumours, 15 (58%) had elevated levels in the Monash assay but only 1 (4%) in the Groome assay (P < 0.001). Among 7 samples from patients with granulosa cell tumours, 100% were elevated in the Monash assay and 71% in the Groome assay (NS, non-significant). In a miscellaneous group of tumours all 8 had elevated levels in the Monash assay and 2 in the Groome assay (P < 0.001). CONCLUSIONS: It was concluded that in normal postmenopausal subjects, INH is generally undetectable or present at low levels, consistent with the loss of ovarian function. The majority of granulosa cell tumours appear to secrete significant amounts of dimeric inhibin-A, whereas mucinous tumours secrete predominantly other forms of INH, presumably related to the alpha-subunit. Serous tumours may also secrete inhibin-related peptides but not dimeric inhibin-A. The nature of the inhibin related peptides produced by epithelial ovarian cancers remains to be characterized.
Adenocarcinoma, Mucinous↗
Oestradiol and immunoreactive inhibin-like secretory patterns following controlled ovarian hyperstimulation with urinary (Metrodin) or recombinant follicle stimulating hormone (Puregon).
Inhibin (and its alpha-subunit) may be of particular value as a marker for follicular development in in-vitro fertilization (IVF) in comparison with the classic follicle stimulating hormone (FSH)-dependent marker oestradiol in patients following pituitary desensitization and treatment with recombinant FSH (rFSH). This preparation lacks luteinizing hormone (LH), which is essential for thecal cell androgen secretion and thus oestradiol production. Our study has assessed oestradiol and immunoreactive inhibin-like secretion following ovarian stimulation with rFSH or a purified urinary FSH preparation (Metrodin) (uFSH). A randomized, assessor-blind study was initiated using patients receiving a single treatment cycle of IVF (using fresh embryos) following pituitary desensitization with intranasal buserelin (500 microg daily) and the i.m. injection of either rFSH (n = 38) or uFSH (n = 17). Ovarian ultrasound examinations were performed and bloods (10 ml) collected prior to FSH treatment and every 1-2 days until ovulation induction with human chorionic gonadotrophin. LH and FSH concentrations were measured by an immunoradiometric assay, and inhibin-like immunoreactivity by a radioimmunoassay and an enzyme-linked immunosorbent assay, both with alpha-subunit specificity. Oestradiol concentration was measured with a coated tube radioimmunoassay. Following desensitization, basal LH, FSH and oestradiol concentrations were measured, as was that of immunoreactive inhibin. Following treatment with either rFSH or uFSH, LH concentrations remained low while FSH concentrations rose to a plateau of 5.6-6.7 IU/l in both groups. In contrast, the concentration of oestradiol was higher (P < 0.05) with rFSH than with uFSH in the last four days of treatment, a pattern that was repeated for inhibin-like immunoreactivity. The change in oestradiol and inhibin concentrations during treatment was approximately 2-fold higher with rFSH. The total number of follicles obtained with rFSH was similar to that with uFSH. However, the number of follicles with a diameter of >/= 15 mm was higher the rFSH group, and there was a concomitant increase in the number of oocytes recovered. Oestradiol concentration and inhibin-like immunoreactivity (determined by either method) were associated with total follicle number and number of follicles >/= 15 mm in diameter, as well as with each other (P < 0.001). When ovarian hormone output was normalized per follicle produced, oestradiol output was higher for rFSH than for uFSH P = 0.04). Inhibin output was clearly higher using rFSH than uFSH. There were seven pregnancies (one miscarriage) with rFSH and two with uFSH. Despite similar concentrations od FSH in patients, rFSH (Puregon) appears to be more potent in vitro in terms of follicular number, ovarian hormone secretion (both concentration and output/follicle) and oocyte recovery. In both groups, LH concentrations of approximately 1.3 IU/l were sufficient to support oestradiol secretion similar to that normally found in IVF programmes using human menopausal gonadotrophin preparations containing large amounts of LH. Despite known problems of specificity with the assays od inhibin, its measurement was of similar value to oestradiol as a marker of follicular development.
Adult↗
Absence of the previously reported G protein oncogene (gip2) in ovarian granulosa cell tumors.
The molecular pathogenesis of granulosa cell tumors of the ovary is not understood, although recent studies have shown that authentic inhibin secretion by these tumors may be used as a tumor marker. G proteins are heterotrimeric membrane-based polypeptides that mediate signal transduction. Activating mutations of the alpha-subunit have been reported in several tumors in which the resulting constitutively activated signal transduction pathway may be involved in tumorigenesis. Activating mutations of the G protein, G alpha I-2, have been reported to be present in 30% of ovarian sex cord tumors and in adrenocortical tumors; this activated G alpha I-2 has been designated the gip2 oncogene. We sought to explore the frequency of this oncogene in granulosa cell tumors, the most common of the sex cord tumors. Genomic DNA was obtained from either fresh-frozen tumor tissue or paraffin-embedded sections. Using both allele-specific oligonucleotide hybridization and direct sequencing of a PCR-amplified region of the G alpha I-2 gene, we were unable to confirm the presence of the previously reported mutation in any of the 13 tumors examined. The gip2 oncogene does not appear to be present at high frequency in ovarian granulosa cell tumors.
Adult↗
Biological and immunological characterization of inhibin forms in human plasma.
A number of immunoassay methods have been developed recently to detect specifically the bioactive alpha-beta A subunit inhibin dimer (inhibin A) in human plasma. However, the specificity of these assays in terms of their ability to detect the range of inhibin forms found in plasma and their relationship to bioactivity have not been investigated. Inhibin was fractionated from human follicular fluid (hFF) and serum/plasma from women stimulated with gonadotropins (IVF serum), and from postmenopausal and male plasma, using a combined immunoaffinity/preparative SDS-PAGE procedure. The molecular weight profile of inhibin was established by inhibin in vitro bioassay, three alpha-beta A subunit specific immunoassays, and three alpha subunit-directed immunoassays that detect the alpha subunit as well as inhibin A and B forms. In hFF inhibin forms of 33, 36, 55 and 66K were detected by in vitro bioassay and by most immunoassays except for 33 k inhibin, which was nondetectable by one alpha-beta A ELISA. The alpha subunit-directed assays also detected activity in the 29-31K region, in some assays in considerably high levels. In IVF serum in vitro bioactivity and immunoactivities were detected between 27 and 100K with the alpha-beta A assays failing to detect all bioactive forms. Alpha subunit-directed assays gave similar immunoactive profiles. Neither in vitro bioassay nor alpha-beta A assays detected activity in post-menopausal plasma or male plasma, while alpha subunit-directed assays showed peaks predominantly at 36 k, although at low levels. It is concluded that dimeric inhibin A specific assays detected bioactive inhibin forms in hFF and to a lesser extent in IVF serum. Alpha subunit-directed assays correlated poorly with in vitro bioassay in hFF because of the high alpha subunit levels in this sample. The higher correlation between these assays in IVF serum suggested that there was little free alpha subunit. The 36K form in male plasma may be free alpha subunit or inhibin B.
Animals↗
The control of ovulation in mothers of dizygotic twins.
Dizygotic twinning is familial, suggesting that there may be an inherited abnormality of the control of ovulation that predisposes to double ovulation and, therefore, dizygotic twins. The present study examines 17 mothers of dizygotic twins (MODZT) and 8 control mothers of singletons by daily blood sampling throughout an entire menstrual cycle. Blood samples were assayed for LH, FSH, estradiol, progesterone, and inhibin. The process of follicular development was followed by transvaginal ultrasound. The pituitary LH response to iv GnRH was also assessed. Three of the 16 MODZT double ovulated during the study compared to none of the 8 control mothers (P < 0.05). The number of small follicles (<6 mm) declined significantly in control women at midcycle, but not in MODZT. There was no significant difference in serum FSH, LH, estradiol, or inhibin levels between the 2 groups at any stage of the menstrual cycle. During the follicular phase, serum progesterone levels were significantly higher in MODZT. The response to GnRH stimulation was not different between MODZT and controls. In conclusion, this study demonstrates an increased tendency to double ovulate in MODZT that may be due to a reduced rate of atresia in advanced follicles. Furthermore, the elevated progesterone levels in MODZT during the follicular phase suggest altered intrafollicular steroidogenesis that is independent of gonadotropins.
Adult↗
Clinical review 82: Androgens and the postmenopausal woman.
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Androgens↗