A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density.

From a longitudinal prospective study, 160 women with spontaneous menopause and without steroid medication were followed during the transition from pre- to postmenopause. After 12 years 152 women were still participating in the study. Blood samples were drawn every 6 months until 1 year after the menopause and every 12 months thereafter. Measurements of bone mineral density (BMD) on the forearm were performed every second year. All women routinely completed a questionnaire concerning symptoms frequently attributed to the climacteric period. All data were grouped around the onset of the menopause, thereby allowing longitudinal evaluation of the changes in the variables from the premenopausal to the postmenopausal period. The beginning of the perimenopausal period was characterized by transitory elevations of follicle-stimulating hormone (FSH). A significant increase in serum levels of gonadotropins was observed for both FSH and luteinizing hormone (LH) from about 5 years before the menopause. Within the 6 month period around the menopause there was a further increase which culminated within the first postmenopausal year for LH and 2-3 years postmenopause for FSH. Thereafter, a continuous decrease in LH occurred over the following 8 years. With respect to FSH, there was a slight decline starting about 4 years postmenopause. During the premenopausal period an increasing frequency of inadequate luteal function or anovulation occurred and, in the postmenopausal years, the serum levels of progesterone (P) were invariably low. Gradually, the ratio between estrone (E1) and 17-beta-estradiol (E2) increased, reflecting the declining follicular steroidogenesis. A marked decrease in estrogen levels occurred during the 6 month period around the menopause, most pronounced in E2. During the next 3 years, the levels of E2 and E1 showed an essentially parallel, moderate decline. Around the menopause, serum levels of testosterone (T), delta4-androstenedione (A) and sex hormone-binding globulin (SHBG) showed small but significant decreases. From about 3 years postmenopause, the levels were relatively constant over the following 5 years. A decrease in BMD was observed in the postmenopause, and from about 3 years postmenopause, estradiol correlated positively with BMD. Before, as well as after the menopause, body mass index (BMI) showed an inverse correlation with SHBG. Postmenopausal androstenedione correlated positively with E1, E2 and T. BMI correlated positively with E1 and E2. The concentrations of the free fraction of E2 and T are dependent on the levels of SHBG, which in turn has a negative correlation with BMI. The impact of this will influence the severity of symptoms, the degree of bone loss and the need for supplementary therapy.

Bone loss in relation to menopause: a prospective study during 16 years.

This prospective study evaluated bone loss in the peri- and postmenopausal period in 156 women followed from age 48 to 64 years. All women were premenopausal at the start of the study. Areal bone mineral density (g/cm(2)) was measured by single-photon absorptiometry (SPA) of the forearm at the 1 cm level (BMD 1 cm) and the 6 cm level (BMD 6 cm) every second year. Onset of menopause (MP) was determined according to the criteria of the World Health Organization (12 months of amenorrhea and elevated follicle-stimulating hormone). At the end of the study, 125 of 156 women (80%) remained. Bone mineral density (BMD) at age 48 years correlated with BMD at age 64 years within the respective region (r = 0.4-0.5, p < 0.001, respectively). There was no BMD loss in the premenopausal period. BMD loss was accelerated at menopause (MP) independent of chronological age. BMD loss was greater during the first 5 years following MP than during the following 6 years (BMD 1 cm 2.4% per year [1.0%-3.9%] vs. 0.4% per year [-0.3%-1.0%], p < 0.01). The quartile of women with late MP (>53.7 years) had greater bone loss during the first 5 years after MP than the quartile of women with early MP (<50.3 years) (p < 0.001). At age 64 years, BMD was no different when comparing the quartile of women with late MP vs. the quartile of women with early MP. Furthermore, there was no correlation between age at menopause and BMD at the age of 64. In summary, among women still menstruating at age 48 years, there was no measurable BMD loss in the premenopausal period. Independent of chronological age, BMD loss accelerated during MP. Rates of loss were highest in the early postmenopausal period. Independent of age at MP, premenopausal women with low age-specific BMD at age 48 years had an increased risk of sustaining low BMD at age 64 years also.

Plasma protein changes induced by two orally administered androgen derivatives.

Epostane is a synthetic 17 alpha-alkylated 5 beta-androstane derivative, active following oral administration and devoid of any apparent androgenic, estrogenic or antiestrogenic potency. Circulating concentrations of 13 different plasma proteins were measured in eight women before and after 2 and 4 weeks of daily oral intake of 600 mg of epostane. The results were compared with those previously found during administration of the same daily dose of danazol, a synthetic 17 alpha-alkylated androgen derivative with known androgenic/anabolic activity. Epostane significantly suppressed serum levels of sex hormone-binding globulin, pregnancy zone protein and thyroxin-binding globulin and increased the levels of transthyretin. Haptoglobins, plasminogen and transferrin showed minor and/or transient changes and the levels of high density lipoproteins, alpha2-macroglobulin, albumin, C1-esterase inactivator, C3 complement and transcortin remained unaffected. The pattern of changes in plasma proteins was almost identical to that induced by administration of danazol, although the effects of epostane were somewhat weaker. Thus epostane is capable of inducing substantial changes in the pattern of steroid-sensitive plasma proteins in an androgen-like fashion despite its apparent lack of androgenic activity. The capacity of a steroid to induce such changes thus seems to be tied to the chemical structure rather than to the intrinsic hormonal activity of the molecule.

Impaired secretory function of the prostate in men with oligo-asthenozoospermia.

The secretory function of the human prostate and the seminal vesicles is a prerequisite for gel formation and liquefaction of semen, but the relation to poor sperm motility and low sperm count in infertile men remains to be clarifyed. Our aim was to evaluate the secretory function of the prostate and the seminal vesicles in normozoospermic men (n = 35) and in asthenozoospermic men, who were all also oligozoospermic (n = 27). All 62 subjects belonged to couples undergoing routine infertility evaluation. In liquefied seminal fluid we measured the concentrations of fructose and protein C inhibitor (PCI) contributed by the seminal vesicles, PCI complexed to prostate-specific antigen (PSA), and the prostatic contribution of zinc, PSA, acid phosphatase (PAP), beta-microseminoprotein (beta-MSP), and Zn alpha 2-glycoprotein (Zn alpha 2-GP). The concentration of each prostatic secretory protein correlated significantly with that of zinc (P < 0.01) in both the normozoospermic (NZS) and oligo-asthenozoospermic (OAZS) subgroups, but the PCI concentration did not correlate significantly with that of fructose. There was no significant difference between the NZS and OAZS subgroups in ejaculate volume or secretory contribution from the seminal vesicles, whereas the OAZS subgroup was characterized by significantly lower secretory contributions of Zn alpha 2-GP (P = 0.001), Zn, PSA, PAP (P < 0.01), and beta-MSP (P < 0.05). The two subgroups did not differ significantly in the serum concentration of luteinizing hormone (LH), testosterone, or sex hormone-binding globulin (SHBG). The results thus suggest the secretory contribution of major prostatic proteins and zinc per ejaculate to be significantly decreased in oligo-asthenozoospermic men. The importance of this finding in relation to poor sperm count and motility as indicators of impaired gonadal function requires further investigation.

A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density.

From a longitudinal prospective study, 160 women with spontaneous menopause and without steroid medication were followed during the transition from pre- to postmenopause. After 12 years 152 women were still participating in the study. Blood samples were drawn every 6 months until 1 year after the menopause and every 12 months thereafter. Measurements of bone mineral density (BMD) on the forearm were performed every second year. All women routinely completed a questionnaire concerning symptoms frequently attributed to the climacteric period. All data were grouped around the onset of the menopause, thereby allowing longitudinal evaluation of the changes in the variables from the premenopausal to the postmenopausal period. The beginning of the perimenopausal period was characterized by transitory elevations of follicle-stimulating hormone (FSH). A significant increase in serum levels of gonadotropins was observed for both FSH and luteinizing hormone (LH) from about 5 years before the menopause. Within the 6 month period around the menopause there was a further increase which culminated within the first postmenopausal year for LH and 2-3 years postmenopause for FSH. Thereafter, a continuous decrease in LH occurred over the following 8 years. With respect to FSH, there was a slight decline starting about 4 years postmenopause. During the premenopausal period an increasing frequency of inadequate luteal function or anovulation occurred and, in the postmenopausal years, the serum levels of progesterone (P) were invariably low. Gradually, the ratio between estrone (E1) and 17-beta-estradiol (E2) increased, reflecting the declining follicular steroidogenesis. A marked decrease in estrogen levels occurred during the 6 month period around the menopause, most pronounced in E2. During the next 3 years, the levels of E2 and E1 showed an essentially parallel, moderate decline. Around the menopause, serum levels of testosterone (T), delta 4-androstenedione (A) and sex hormone-binding globulin (SHBG) showed small but significant decreases. From about 3 years postmenopause, the levels were relatively constant over the following 5 years. A decrease in BMD was observed in the postmenopause, and from about 3 years postmenopause, estradiol correlated positively with BMD. Before, as well as after the menopause, body mass index (BMI) showed an inverse correlation with SHBG. Postmenopausal androstenedione correlated positively with E1, E2 and T. BMI correlated positively with E1 and E2. The concentrations of the free fraction of E2 and T are dependent on the levels of SHBG, which in turn has a negative correlation with BMI. The impact of this will influence the severity of symptoms, the degree of bone loss and the need for supplementary therapy.

Relationship between serum testosterone and sex hormone binding globulin in menstruating and postmenopausal women.

The relationship between total testosterone (T), sex hormone binding globulin (SHBG) and calculated non-SHBG-bound testosterone (NST) was studied in randomly collected blood samples from healthy menstruating (n = 61) and postmenopausal (n = 65) women. In 12 of the menstruating women, blood samples were also collected more frequently during the menstrual cycle. Total T and SHBG were positively correlated in menstruating women in random samples as well as during different phases of the menstrual cycle, but not in postmenopausal women. Upper and lower limits of NST were independent of SHBG in menstruating but not in postmenopausal women. The data are at variance with the common concept about SHBG regulation and suggest a kind of compensatory mechanism in order to maintain a constant androgen homeostasis in menstruating but not in postmenopausal women. Consequently, supranormal total T or subnormal SHBG values do not necessarily indicate hyperandrogenicity in normally menstruating women.

Beta microseminoprotein is not a prostate-specific protein. Its identification in mucous glands and secretions.

Beta microseminoprotein (beta inhibin, PSP94), an unglycosylated protein of 94 amino acids with unknown function, is one of the predominating proteins in the secretion of the human prostate gland. In this work the authors have demonstrated that the expression of beta microseminoprotein is not restricted to the prostate and that the protein has a previously unrecognized widespread occurrence in the human body. According to radioimmunoassay, beta microseminoprotein immunoreactivity is present in many nonprostatic body fluids. The highest concentrations were found in secretions from the respiratory tract; in tracheobronchial fluid sometimes even at concentrations comparable to that in seminal plasma (about 1 g/l). Intermediate concentrations were found in gastric juice and some samples of secretion from the uterine cervix, whereas tears, saliva, pancreatic juice, bile, and mucus from the colon had low concentrations. According to gel chromatography, the molecular size of the beta microseminoprotein immunoreactivity present in tracheal fluid, gastric juice, and secretion from the uterine cervix did not differ from that of beta microseminoprotein in seminal plasma. The beta microseminoprotein immunoreactive component present in gastric juice had the same amino-terminal amino acid sequence as prostatic beta microseminoprotein (14 residues identified in material purified from gastric juice), providing further evidence for chemical identity of a nonprostatic beta microseminoprotein with the prostatic protein. Immunohistochemical staining with affinity-purified antibodies demonstrated the presence of beta microseminoprotein in many tissues, including the goblet cells in the tracheobronchial epithelium, tracheobronchial submucosal glands, certain mucosal cells in the antrum of the stomach, some glands of Brunner in the duodenum, and in parts of the mucosa of the colon. At least in the respiratory tract, the staining was localized to mucus-containing cells. beta microseminoprotein immunoreactivity also was localized to the cilia of the ciliated epithelium in the respiratory tract, the fallopian tubes, and the Gartner ducts of the uterine cervix. The pattern of tissue distribution of beta microseminoprotein found in this work indicates a connection of beta microseminoprotein with mucous secretions.

Relationship between serum testosterone and sex hormone-binding globulin in adult men with intact or absent gonadal function.

Serum levels of testosterone and sex hormone-binding globulin (SHBG) were determined in 80 apparently healthy men aged 25-85 years and in 23 patients with prostatic carcinoma (CAP) aged 60-75 years before and 6 months after orchidectomy. Serum levels of testosterone and SHBG were correlated positively in healthy men, in all subjects overall as well as within different age groups, and in CAP patients before, but not after, orchidectomy. These data are not consistent with the classical theory regarding SHBG regulation and also speak against an influence of SHBG binding on testosterone metabolism as a mechanism behind the observed positive association between testosterone levels and SHBG.

Decreasing serum levels of sex hormone-binding globulin around the menopause and temporary relation to changing levels of ovarian steroids, as demonstrated in a longitudinal study.

Blood samples collected longitudinally in 17 women over a period of 3 years, starting 11/2 years before the menopause, were assessed for sex hormone-binding globulin (SHBG), 17 beta-estradiol (E2), progesterone, and total testosterone. A slight (7.2%) decrease in mean SHBG from 4.25 +/- 1.67 (standard deviation) mg/l to 3.95 +/- 1.61 mg/l was observed within the 6-month period encompassing the menopause. More specifically, the decrease appeared to commence at the menopause and to become clearly significant (P = 0.01) some 2 to 6 months later. During the subsequent year, a further decrease to 3.64 +/- 1.42 mg/l was observed, amounting to a total decrease in mean SHBG by 14.4% (P less than 0.001). Of the hormones, only E2 exhibited a marked decrease (P less than 0.01) within this same 6-month period. The changes in SHBG during the 6-month transition period from premenopause to postmenopause correlated significantly (P = 0.013) only with those of E2. It is concluded that decreasing E2 levels appear to play a significant role in the downward modulation of SHBG levels commencing at the menopause.

Sex steroids and steroid binding proteins in primary biliary cirrhosis.

In a longitudinal study on sex steroids and steroid binding proteins in primary biliary cirrhosis (PBC), 9 female patients were compared with 27 strictly age-matched healthy controls. In the patients we found elevated levels of androstenedione and, in advanced disease, of testosterone. Levels of total oestrone, dehydroepiandrosterone and dehydroepiandrosterone sulphate (DHAS) were not significantly different from controls, although numerically lower values were noted for the two later steroids in the PBC patients. The mean albumin level in the PBC patients was at the lower reference limit. A significant positive correlation between DHAS and albumin was found in the patients. The levels of sex hormone binding globulin (SHBG) were elevated in the patients and increased further with progressive disease as measured by N-demethylating capacity. The results suggest a close association, unrelated to sex hormone levels, between increased SHBG synthesis and progressive hepatocellular failure in PBC.

Dehydroepiandrosterone sulfate in postmenopausal women: lack of influence of parity.

Serum concentrations of dehydroepiandrosterone sulfate (DHAS) were analyzed in 251 healthy, medicine-free postmenopausal women 46-65 years of age. Twentyfour of the women were nulliparous and 227 parous (1- to 7-parous). There was no association, whatsoever, between parity and DHAS levels. The data are at variance with previous findings in menstruating women of higher DHAS levels in nulliparous than in parous women. This difference between menstruating and postmenopausal women may reflect an influence of age per se on DHAS metabolism. It may also reflect the exclusion in this study of women with i.e. endometrial hyperplasia/cancer, diseases often associated with elevated DHAS levels and increased risk for nulliparous women.

Dehydroepiandrosterone sulphate and dehydroepiandrosterone in serum: differences related to age and sex.

Serum concentrations of dehydroepiandrosterone sulphate (DHAS) were determined in 590 healthy women aged 20-87 yr. Simultaneous assays of dehydroepiandrosterone (DHA) were performed in 417 of the women. DHA and DHAS levels correlated negatively with age while the DHA/DHAS ratio proved to be unrelated to age. When values for 60 healthy men in the age range 20-84 yr were compared with those obtained in 60 randomly-selected healthy women who were exactly age-matched, the DHAS levels were found to be significantly lower and the DHA/DHAS ratios significantly higher in the women. These results might be of use in establishing normal clinical ranges for serum DHA, DHAS and the DHA/DHAS ratio in women.

Epostane in nonpregnant females: effects on progesterone, 17 alpha-hydroxyprogesterone, and 17 beta-estradiol of two dose levels given for one month.

So far, the use of epostane, a relatively new inhibitor of 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase enzyme system (3 beta-HSD), has been confined to short-term interference with luteal and placental function. This study explored whether epostane treatment from the beginning of the cycle for approximately 1 month would also inhibit ovarian follicular function. Twenty females with regular cycles received epostane 150 mg/day (ten healthy volunteers) or 600 mg/day (ten patients with endometriosis). Blood samples were drawn three times per week during control and treatment cycles. At 150 mg/day the mean total area under the serum concentration curve (AUC) of estradiol (E2) was somewhat higher than during the control cycles, despite apparently lower preovulatory E2 surges. During medication the highest value of E2 was found during the luteal phase. The mean AUC of progesterone (P) and 17 alpha-hydroxyprogesterone (17-OHP) during the luteal surge was decreased by approximately 45% each. At 600 mg/day all evaluable patients had lower AUC of E2 than during the control cycle. The mean decrease in AUC of P and 17-OHP was much more pronounced than in the lower dose group. Six of the ten patients showed no hormonal signs of follicular development and, consequently, anovulation. The capacity of epostane to modulate or inhibit, depending on the dose, ovarian follicular steroidogenesis and ovulation may prove valuable in a variety of clinical conditions.

Seminal vesicle-secreted proteins and their reactions during gelation and liquefaction of human semen.

The comparison of measurements of fibronectin and lactoferrin in ejaculates from vasectomized men, subjects with functional deficiency or aplasia of the seminal vesicles, and reference subjects provided evidence that both the fibronectin and the lactoferrin in human seminal fluid originate from the seminal vesicles and the ampullae. The fibronectin is incorporated in the framework of the seminal gel formed during the immediate postejaculatory phase, whereas the lactoferrin remains in solution. In the seminal gel fibronectin is linked to its predominant structural protein, a high molecular weight seminal vesicle protein (semenogelin). Both the gel-bound fibronectin and semenogelin are progressively fragmented and solubilized by the abundant prostatic kallikrein-like protease (prostate-specific antigen) during and after seminal gel liquefaction. Lactoferrin remains essentially unaffected by the seminal proteases.

Free testosterone and testosterone/SHBG index in hirsute women: a comparison of diagnostic accuracy.

Serum levels of sex hormone binding globulin (SHBG), total testosterone (T), free testosterone (fT), 4-androstene-3,17-dione (A-4) and dehydroepiandrosterone sulfate (DHAS) were determined in 30 patients with the polycystic ovary syndrome. Subnormal levels of SHBG were found in 60% of the patients. Elevated levels of T were found in 53%, of fT in 53%, of the T/SHBG ratio in 90%, of A-4 in 75% and of DHAS in 36% of the patients. The better diagnostic accuracy of the T/SHBG ratio compared to fT may be explained by the regulatory effect of SHBG binding upon the albumin-bound fraction of T, which may be another biologically active T fraction. It is concluded that the assay of fT does not offer any further diagnostic advance compared to conventional determinations of T. Assays of fT do not provide any information about the origin of the elevated levels of biologically active androgen.

A prospective long-term study in women from pre-menopause to post-menopause: changing profiles of gonadotrophins, oestrogens and androgens.

To permit a more detailed hormonal characterization of the peri-menopause, 30 healthy women were examined at regular intervals over a 7-yr period, starting about 3 yr before the menopause. Even though most of the subjects periodically experienced climacteric symptoms, no hormonal supplementation was given. The serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), oestradiol and oestrone that were recorded essentially confirmed previous data obtained in cross-sectional studies. Within the 6-mth period around the menopause the serum levels of testosterone and androstenedione showed small but significant decreases of 18 and 16%, respectively. These decreases continued over the following years and amounted to about 30% after 3 yr. In contrast, neither the mean level of dehydroepiandrosterone (DHA) nor the DHA/DHA sulphate (DHAS) ratio changed significantly at the menopause, but DHA and DHAS concentrations declined slowly by about 20% over the 7-yr observation period. The mean level of DHAS showed an isolated increase during the last few months before the menopause. A similar, although not significant, increase was also seen in DHA and testosterone levels. After the first post-menopausal year a significant positive correlation was found between the levels of oestrone and androstenedione. This longitudinal study of individual women appeared to lend itself well to the investigation of even subtle hormonal fluctuations during the gradual transition to an established post-menopausal pattern.

Sex steroids and steroid binding proteins in female alcoholic liver disease.

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

Radioimmunoassay of human sex hormone binding globulin: improved radioiodination procedure.

Sex hormone binding globulin (SHBG), purified by affinity chromatography from retroplacental blood plasma, was reacted with 3-(p-hydroxyphenyl) propionic acid N-hydroxysuccinimidyl ester (PHPPS, Bolton-Hunter reagent). The derivative of SHBG obtained (parahydroxyphenylpropionyl-SHBG; PHPP-SHBG) was stable and could, in contrast to underived SHBG, be efficiently 125I-iodinated with a lactoperoxidase technique. The PHPP-SHBG labelled with 125I had good antiserum binding and stability properties and was used for radioimmunoassay (RIA) of SHBG in serum. The RIA requires a total incubation time of 3 h. It has been standardized with purified SHBG and has a sensitivity of 5 micrograms/l, giving a lowest detectable concentration in the routine procedure (samples diluted 1:40) of about 0.2 mg/l. Variation within and between assay was 4.1% and 7.2%, respectively, for samples with values within the normal range. Values obtained by this RIA procedure correlate well with those obtained by a dihydrotestosterone binding method and by an electroimmunoassay technique. The mean serum concentration of SHBG in healthy, regularly menstruating women (n = 42) was 3.7 +/- 1.0 (SD, standard deviation) mg/l and in healthy men (n = 100) 2.0 +/- 0.9 mg/l.