A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition

The aims of this study were to describe, in relation to date of final menses, the average androgen levels of women in the years before and after this date, and to determine the extent to which these average levels were dependent on age and body mass index (BMI) and the degree of tracking in residual androgen levels, or the extent to which individuals above (below) the mean for their age or time relative to final menstrual period (FMP) and BMI remain above (below) the mean as time progresses. Serial levels of serum sex hormone-binding globulin (SHBG), testosterone (T), and dehydroepiandrosterone sulfate (DHEAS) were measured annually in 172 women from the Melbourne Women's Midlife Health Project who experienced a natural menopause during 7 yr of follow-up. Fasting blood samples were drawn between days 4-8 if women were still menstruating or after 3 months of amenorrhea. The free androgen index (FAI) was calculated as the ratio ofT to SHBG x 100. Means of the log-transformed androgen levels were analyzed as a double logistic function of time relative to FMP as well as age and BMI, and correlations between repeated androgen levels were measured. Mean SHBG levels decreased by 43% from 4 yr before to 2 yr after the FMP. The time of most change was 2 yr before FMP [95% confidence interval (CI), 0.8-3.2]. SHBG levels were, on the average, 5% lower for each halving of estradiol (E2) levels and 4% lower for each kilogram per m2 of BMI (P < 0.0001). About one third of the decline in SHBG was explained by E2 and BMI. After adjusting for all variables, SHBG showed strong tracking. Mean T levels did not vary with time relative to FMP and were independent of age and BMI. Residual values of T showed weak tracking. The FAI increased by 80% from 4 yr before FMP to 2 yr after FMP, and changed maximally 2.2 yr before FMP (95% CI, 1.2-3.2). The FAI was not related to age or E2, but was, on the average, 4% higher for each kilogram per m2 of BMI (P < 0.0001). Residual values of FAI showed moderate tracking. Mean DHEAS levels were not related to the FMP, but were 1.5% lower for each year of age (P < 0.01) and 3.8% lower for each kilogram per m2 of BMI (P < 0.0001). Residual values of DHEAS showed strong tracking. It is concluded that SHBG and FAI levels change at the time of the menopause, at least partially due to the decline in E2. DHEAS decreases as a function of age, not time relative to FMP, and T remains unchanged during the menopausal years. SHBG and DHEAS show a high degree of stability within an individual over time.     

Anti-mullerian hormone and inhibin B in the definition of ovarian aging and the menopause transition

Context/Objective: The objective of the study was to determine whether anti-Mullerian hormone (AMH) and inhibin B are viable endocrine biomarkers for framing the menopause transition from initiation to the final menstrual period (FMP). Design: We assayed AMH, inhibin B, and FSH in 300 archival follicular phase specimens from 50 women with six consecutive annual visits commencing in 1993 when all women were in the pre- and perimenopausal menopause stages. Subsequently each woman had a documented FMP. The assay results were fitted as individual-woman profiles and then related to time to FMP and age at FMP as outcomes. Results: Based on annual values from six time points prior to the FMP, (log)AMH longitudinal profiles declined and were highly associated with a time point 5 yr prior to FMP [including both observed and values below detection (P < 0.0001 and P = 0.0001, respectively)]. Baseline AMH profiles were also associated with age at FMP (P = 0.035). Models of declining (log)inhibin B profiles (including both observed and values below detection) were associated with time to FMP (P < 0.0001 and P = 0.0003, respectively). There was no significant association of (log)inhibin B profiles with age at FMP. Conclusions: AMH, an endocrine marker that reflects the transition of resting primordial follicles to growing follicles, declined to a time point 5 yr prior to the FMP; this may represent a critical biological juncture in the menopause transition. Low and nondetectable levels inhibin B levels also were observed 4-5 yr prior to the FMP but were less predictive of time to FMP or age at FMP.     

Change in estradiol and follicle-stimulating hormone across the early menopausal transition: effects of ethnicity and age

Serum reproductive hormone concentrations were measured longitudinally in a community-based, multiethnic population of midlife women to assess whether ethnic differences exist in the patterns of change in estradiol (E2) and FSH and, if so, whether these differences are explained by host characteristics. We studied 3257 participants from seven clinical sites in the Study of Women's Health Across the Nation (SWAN) who were aged 42-52 yr at baseline and self-identified as African American (28.2%), Caucasian (47.1%), Chinese (7.7%), Hispanic (8.4%), or Japanese (8.6%). E2 and FSH were assayed in serum collected primarily in the early follicular phase of a spontaneous menstrual cycle in three consecutive annual visits. The primary explanatory variables included in repeated-measures regression analyses were race/ethnicity, menopausal status, age, body mass index (BMI), day of the cycle, smoking, parity, socioeconomic status, study site, and the self-report of diabetes at baseline. At the baseline visit, 46.2% of the women were classified as being early perimenopausal, with the remaining being premenopausal. By the second follow-up visit, 5.5% of the women in that cohort were postmenopausal, 66.8% were early perimenopausal, 8.3% were late perimenopausal, and 19.4% remained premenopausal. Serum E2 concentrations decreased significantly with age, with a steeper decline at higher ages. FSH concentrations increased significantly with age, with a steeper increase at higher ages. Similar patterns in the decline of E2 and the increase in FSH with age were found across ethnic groups, but the levels of these hormones differed by race/ethnicity. Specifically, over time, Chinese and Japanese women had lower E2 concentrations but similar FSH levels, compared with Caucasian women, and African American women had higher FSH concentrations but comparable E2 levels with those of Caucasian women. These ethnic differences in E2 and FSH were independent of menopausal status. The effect of BMI on serum E2 and FSH levels varied by menopausal status. Increasing BMI was associated with decreasing concentrations of E2 among premenopausal and early perimenopausal women but was associated with increasing concentrations of E2 among late perimenopausal and postmenopausal women. Increasing BMI was associated with decreasing concentrations of FSH, with the effect of BMI becoming larger as women transitioned through menopause. We conclude that serum E2 levels decrease and FSH concentrations increase with increasing age in midlife women, that ethnic differences in E2 over time differ from ethnic differences in FSH and suggest ethnic differences in the pituitary-ovarian relationship, and that the effect of BMI on E2 and FSH concentrations varies by menopausal status.     

The menopausal transition: analysis of LH, FSH, estradiol, and progesterone concentrations during menstrual cycles of older women.

Studies of menstrual cycle length in large populations demonstrated that there is a striking increase in the variability of intermenstrual intervals just before menopause. The changes in serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), and progesterone (P) during menstrual cycles in a group of perimenopausal women were compared with the findings in young normal women. In 8 women, 46-56 years old with regular cycles, cycle length was shorter and the mean E2 concentration was lower than in younger women. There was a striking increase in FSH concentration throughout the cycle while LH remained in the normal range. In 2 women, 14 cycles of variable length were studied during 2 years of the menopausal transition. In some instances, hormonal changes associated with follicular maturation and corpus luteum function occurred in the presence of high, menopausal levels of LH and FSH with a diminished secretion of E2 and P. In others vaginal bleeding occurred during a fall in serum E2 with no associated rise in P. Cycles of variable length during the menopausal transition may be due either to irregular maturation of residual follicles with diminished responsiveness to gonadotropin stimulation, or to anovulatory vaginal bleeding that may follow estrogen withdrawal without evidence of corpus luteum function. The observation of elevated FSH concentrations and normal LH levels in perimenopausal women emphasizes the complexity of the hypothalamic-pituitary-ovarian regulatory system and suggests that LH and FSH are modulated independently at the level of the pituitary.     

Inhibin B and anti-Müllerian hormone, but not testosterone levels, are normal in infants with nonmosaic Klinefelter syndrome

Klinefelter syndrome is a major cause of infertility in the male. Nevertheless, pregnancies were recently obtained by intracytoplasmic injection of sperm retrieved by surgery or ejaculation, underscoring the need to understand the role of Sertoli and Leydig cell secretions during development. In 18 infants with prenatally diagnosed homogenous 47,XXY karyotype, blood samples were taken from birth to 3 yr of age. Inhibin B (INHB), anti-Müllerian hormone (AMH), testosterone, FSH, and LH levels were compared with those in six adolescents with XXY karyotype and reference values established in 215 control infants. In XXY infants FSH, LH, INHB, and AMH did not differ from controls. Testosterone levels during the first trimester exhibited a physiological increase but were lower than in controls (P = 0.0001). Significant correlations were found between testosterone and LH (P < 0001), between INHB and FSH (P = 0.0011), and between AMH and INHB (P = 0.025). In XXY adolescents, AMH and INHB were undetectable. Our findings demonstrate that testosterone secretion is impaired in infants with Klinefelter syndrome. By contrast, INHB and AMH secretions were not altered, which raises the question of the mechanism(s) governing the decline of Sertoli cell function after puberty.     

Self-adjusted postmenopausal hormone replacement therapy: effects on the biological and immunological profile of FSH and correlation to climacteric symptoms

OBJECTIVE: The purpose of the present study was to evaluate the hormonal profile of patients of postmenopausal age during estrogen replacement therapy (ERT) with special reference to the serum levels of biologically active FSH (B-FSH) in a self-adjusted ERT model. DESIGN: The hormonal values found have been correlated to climateric symptoms reported by the patients (scored by the Kupperman menopausal index (KI)). METHODS: B-FSH was measured using an assay based on a cell system transfected permanently with FSH receptor cDNA. All women (n=32) applied estradiol percutaneously using 1 mg estradiol-17beta (E(2)) as an initial dose and were encouraged to increase the daily dose until they felt comfortable according to a specific scheme. Twelve of the 32 women were hysterectomized and treated, accordingly, with ERT only; 20 women received megestrol acetate monthly for 10 days. RESULTS: The initial average KI was 30 (range 10-54). A high degree of correlation (r=0.83; P<0.001) was observed between B-FSH and immunologically active FSH (I-FSH). Serum I-FSH and E(2) correlated negatively (r=-0.21; P<0.001); similarly, a negative correlation (r=-0.15; P<0.01) was observed between serum B-FSH and E(2) levels. Serum I-FSH and KI showed modest but significant positive correlation (r=0.13; P<0.01); a somewhat higher degree of correlation (r=0.19; P<0.005) was observed when B-FSH and KI were compared. E(2) showed positive correlation to serum sex-hormone binding globulin levels (r=0.22; P<0.001). CONCLUSIONS: This study shows that the transdermal self-adjusted hormone replacement therapy (HRT) model introduced is suitable for studies on endocrine changes during postmenopausal ERT. The finding of poor correlation between serum E(2) levels and KI emphasizes the importance of hormonal measurements during postmenopausal HRT.     

Association between hyperinsulinemia and endogenous androgen levels in peri- and postmenopausal women

We evaluated the relationship between hyperinsulinemia and anthropometric, metabolic, and hormonal parameters that might contribute to the risk for coronary heart disease (CHD) in 104 peri- and postmenopausal women. Plasma glucose, insulin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), sex hormone-binding globulin (SHBG), and total testosterone (TT) were determined. Free androgen index (FAI) and fasting insulin to glucose ratio (IGR) were calculated. The cut off point to define hyperinsulinemia was established at 23 microIU/mg. Mean age was 54.8 years. Mean age at menopause was 47.7 years. Body mass index (BMI) was greater than 25 in 46 patients, and 28 (26.9%) were hyperinsulinemic. BMI, waist circumference, triglycerides, and 2-hour postglucose insulin levels were significantly higher in hyperinsulinemic patients. Hyperinsulinemic patients had higher TT levels (P =.02), FAI (P =.0001), and lower SHBG levels (P =.003). Positive correlations were observed between IGR and BMI, waist-to-hip ratio (WHR), waist circumference, and triglycerides. IGR and high-density lipoprotein-cholesterol (HDL-C) were negatively correlated. IGR presented a positive association with TT and FAI and a negative association with SHBG. FAI contributed positively to IGR, independently of BMI, age, or time since menopause. In conclusion, androgen levels may be important determinants of risk factors for cardiovascular diseases in peri- and postmenopausal women. However, this observation should be confirmed by longitudinal studies.     

Pituitary-ovarian function before, during and after the menopause: a longitudinal study

The excretion of FSH, LH, oestrogens and pregnanediol was monitored once weekly in urine samples collected from eight peri-menopausal women aged 44-55 years (median, 52 years). Observations were commenced between 5 and 15 weeks before the menopause and were continued for 22-30 weeks after final menstruation. Amenorrhoea of greater than 2 years duration in association with a persistent elevation in gonadotrophin output was considered proof of the post-menopausal state. No clear hormonal change occurred at the time of the menopause. During the peri-menopause there is a transition from the regular ovulatory cycles of pre-menopausal women to the unvarying high gonadotrophin and low oestrogen excretion which is generally regarded as being characteristic of post-menopausal women. In the group studied, post-menopausal levels of FSH and LH were common before and episodes of high oestrogen excretion were not uncommon after final menstruation. Menstrual failure appeared to occur spontaneously at some stage during the transition from the pre- to the post-menopausal state, and not to be associated with its conclusion. From the hormonal point of view the immediately post-menopausal period could not be distinguished from the long cycles of peri-menopausal women. This suggests that an endometrial rather than a hormonal event might determine the time at which menstruation stops during the menopausal transition.     

Hormonal profile in anorexia nervosa under control. Correlations with various somatic factors

In order to precise the hormonal pattern of Anorexia Nervosa (AN) at its state phase, we assessed serum estradiol (E2), triiodothyronine (T3), LH and FSH, the maximum increments of their response to 100 microgram LHRH (delta LH and delta FSH) and the ratio of these increments (delta LH/delta FSH). These data were compared with those obtained in 10 normal women assessed at the early follicular phase (Student's test). Furthermore in 20 cases, we assessed LH and FSH during 5 days after a 20 mg IV injection of PREMARIN. E2, T3, LH and FSH are often decreased in AN. On the average, this decrease is very significant for the 3 first ones (p less than 0.001), and slightly significant for FSH (p less than 0,05). The LHRH-response is variable, with an inversion of the LH/FSH ratio as before the puberty in 56% of the cases. On the average, FSH-response is increased (p less than 0,05), and LH-response is normal. The response is delayed for the both gonadotropins. After PREMARIN, the 2 gonadotropins rarely clearly decrease (twice for LH and 5 times for FSH). There is a LH peak only in 3 cases. In order to specify the origin of these anomalies, we searched correlations between 11 hormonal data and some somatic parameters : weight, time, menstrual antecedents. We found 26 statistically significant correlations (12 times p less than 0,05- 5 times p less than 0,001- 9 times p less than 0,001). The following correlations are significant : E2 and LH, E2 and the maximal decrease of LH after PREMARIN (negative correlation), T3 and FSH, delta LH, and delta FSH, duration of the amenorrhea and T3, FSH and delta FSH, the weight and delta LH, the weight and delta LH/delta FSH, weight/height and delta LH/delta FSH, the menstrual antecedents and FSH. So, somatic factors strongly influence the hormonal pattern at the AN-state phase. The weight-decrease, the T3-decrease, and above all the E2-decrease which is independent of the previous ones seem to be the determining elements of the AN-hormonal pattern at this phase.     

Gonadotropin, ACTH, prolactin, sexual steroid and cortisol levels in postmenopausal women's cerebrospinal fluid (CSF)

In CSF and serum of 24 fertile (34.9 +/- 12.2 years) and 15 postmenopausal (58.9 +/- 6.9 years) female patients with non-inflammatory neurologic diseases, LH, FSH, ACTH, prolactin (Prol), estradiol (E), progesterone (P), testosterone (T), and cortisol (C) levels were determined by RIA. In postmenopause, serum levels of FSH and LH had 8- and 6-fold increases in comparison to those in reproductive age. In postmenopause, serum levels of E, P, ACTH and Prol had 8-, 5-, 3- and 2-fold decreases. Serum levels of T and C remained statistically unchanged during the whole life span. In postmenopause, CSF levels of FSH and LH had 3- and 2-fold increases, while E, P, Prol, ACTH CSF levels remained statistically unchanged compared to those in reproductive age (CSF-C levels were under the test sensitivities). CSF/serum ratio of FSH had a 4-fold decrease while that of E had a 4-fold increase in the postmenopause. CSF and serum levels of estradiol and ACTH as well as the logarithmic values of FSH, Prol and P concentrations correlated significantly regarding the whole reproductive postmenopausal life span, however, the CSF-blood barrier seemed to protect the brain from the effects of peripheral estradiol-progesterone deficiencies.     

Roles of estradiol and progesterone in eiliciting the midcycle luteinizing hormone and follicle-stimulating hormone surges.

The positive feedback effects of estradiol (E2) and progesterone (P) on LH and FSH release were studied under novel experimental conditions in three women of reproductive age who had undergone oophorectomy and received uninterupted E2 replacement by subdermal implants. Basal serum E2 levels were in the midfollicular phase range, while LH and FSH levels were normal or slightly elevated. Each volunteer underwent seven experiments at 2- to 4-week intervals, receiving im injections of increasing amounts of estradiol benzoate (E2B) alone and in combination with P. The time and dose of P (administered via P-impregnated polysiloxane intravaginal rings) were varied. In two of the seven experiments, P was given without E2B injections. In all three subjects, increasing serum E2 levels mimicking the preovulatory E2 peak were followed by a surge of LH but not of FSH. However, when serum P levels rose after an increase in serum E2 concentrations had occurred, the LH surge occurred earlier and was accompanied by an FSH peak. When serum P levels rose before serum E2 concentrations had risen or when P levels increased without a rise in serum E2, neither a serum LH nor FSH peak was observed. When administered concomitantly, E2B and P suppressed FSH but not LH levels, while P alone did not affect serum LH or FSH concentrations. These data indicate that an acute rise in serum E2 is a necessary condition for the midcycle LH and FSH surges, that P facilitates or blocks the positive feedback response of gonadotropin release in a time-dependent manner, and that P is required for the preovulatory FSH peak.     

Serum FSH level is lower in dysovulating than in ovulating non-PCOS obese women,independently of body mass index

ObjectivesThe prevalence of ovulation disorder (OD) is 3-fold higher in obese than normal-weight women. Most ODs are associated with concomitant polycystic ovary syndrome (PCOS), but obesity by itself can cause OD, through mechanisms that remain poorly documented. The literature on obese non-PCOS women with OD is sparse. The aim of the present study was to analyze a population of obese non-PCOS women with OD to shed further light on the mechanism of ovulation disorder.Material and methodsThis retrospective observational study of infertile obese women without PCOS compared a control group without OD (n = 45) to a study group with OD (n = 30) (OD group). Clinical, hormonal, and ultrasound characteristics were collected between cycle days 2 and 5. Women older than 37 years and women with PCOM (polycystic ovarian morphology) or hormonal disorder were excluded.ResultsBody mass index (BMI) was significantly higher in the OD group, as were waist circumference and insulin and leptin serum levels. Conversely, serum follicle stimulating hormone (FSH) levels were significantly lower. After adjustment for BMI, only serum FSH level remained significantly different between the 2 groups. Discriminant analysis suggested that FSH may have a much stronger effect on OD than BMI.ConclusionLow serum FSH level may contribute to OD in some obese women, independently of BMI. The pathophysiological mechanism of this finding and its impact on therapeutic strategies must be clarified.     

The relationship of circulating dehydroepiandrosterone,testosterone, and estradiol to stages of the menopausal transition and ethnicity

In this report, 3029 women between the ages of 42 and 54 yr from five ethnic groups were studied for 2 yr. Log circulating dehydroepiandrosterone sulfate (DHEAS) concentrations were highest among Chinese and Japanese and lowest among African Americans and Hispanics, and this pattern persisted after adjustment for age, smoking, and log body mass index (BMI). With the exception of Japanese women, log BMI was negatively related to log circulating DHEAS. The magnitude of this association varied by ethnic group, and the decline in log circulating DHEAS levels with higher log BMI was steepest for Chinese and least steep for Hispanics. The relationship between log DHEAS and log BMI was positive for Japanese. DHEAS levels did not decline at a steady rate during the menopausal transition and transiently increased in some women and increased, on average, during the transition to late perimenopause. These increases tended to be larger for Chinese, Hispanic, and Japanese than for African Americans and Caucasians, although the interactions were not statistically significant. Changes in circulating testosterone and, to a lesser extent, estradiol were correlated to changes in DHEAS. These data have importance in understanding the endocrinology of the menopausal transition, defining the relationship of adrenal steroid production during declining ovarian function and determining a rationale regarding DHEAS supplementation for older women.     

Negative feedback effects of gonadal steroids are preserved with aging in postmenopausal women

There is now evidence for alterations in the neuroendocrine control of the reproductive axis with aging, but its sensitivity to gonadal steroid negative feedback remains controversial. To examine the independent effect of age and gonadal steroid negative feedback, younger (45-55 yr; n = 7) and older (70-80 yr; n = 6) postmenopausal women (PMW) were studied at baseline on no HRT, after 1 month of transdermal estrogen (50 microg/d; E) and again after a further month of E and 7 d of transvaginal progesterone (P) (100 mg bid; E + P). At each admission, blood was sampled every 5 min for 8 h for measurement of gonadotropin free alpha-subunit (FAS), which was used as a marker of GnRH pulse frequency. LH and FSH were measured in pooled samples. Midfollicular and midluteal phase levels of E2 and P were achieved during the E and E + P treatments and were not different between younger and older PMW. There was a negative feedback effect of E and E + P on mean LH (P < 0.0001) and an additional effect of age (P < 0.003), with older women having lower values throughout. Mean FSH was also decreased with E and E + P (P < 0.0001) and was consistently lower in the older women (P < 0.05). Mean FAS levels decreased with hormonal treatment (P < 0.0001) and age (P < 0.001), but the effect of hormonal treatment was attenuated in the older group (P < 0.005). FAS pulse frequency was unchanged with addition of E, but dramatically decreased with E + P (P < 0.002). Both hormonal replacement (P < 0.05) and age (P < 0.005) decreased FAS pulse amplitude, an effect that was attributable entirely to E as there was no additional change with E + P. These studies indicate that: 1) both age and gonadal steroids independently decrease mean LH, FSH, and FAS in PMW; 2) responsiveness to steroid negative feedback on FAS is attenuated with aging in absolute but not relative terms, whereas the effect on mean levels of LH and FSH is clearly preserved; and 3) FAS pulse frequency is unchanged with E2 administration but decreases dramatically with addition of P in both old and young PMW.     

Regulation of follicle-stimulating hormone beta and common alpha-subunit messenger ribonucleic acid by gonadotropin-releasing hormone and estrogen in the sheep pituitary

The effect of gonadotropin-releasing hormone (GnRH) and/or estradiol (E2) on pituitary messenger ribonucleic acid (mRNA) levels of luteinizing hormone beta (LH beta), follicle-stimulating hormone beta (FSH beta) and the common alpha-subunit were determined in anterior pituitary glands from ovariectomized (OVX) ewes. Hypothalamo-pituitary disconnected (HPD) ewes receiving appropriate hormonal treatment were used to assess the relative roles of GnRH and E2 in directly regulating FSH beta and alpha-subunit mRNA levels. Levels of LH beta mRNA were increased in OVX animals compared with intact controls, and E2 treatment of OVX animals significantly reduced mRNA levels of LH beta and FSH beta. HPD substantially reduced FSH beta and alpha-subunit mRNA levels. Treatment of OVX/HPD animals with pulses of GnRH (250 ng/2 h) for 1 week restored FSH beta and alpha-subunit mRNA to OVX levels. Combined GnRH and E2 treatment significantly lowered FSH beta mRNA levels, but resulted in a rise in alpha-subunit mRNA levels. Treatment of OVX/HPD ewes with E2 alone had no effect on FSH beta and alpha-subunit mRNA levels. These findings indicate that E2 acts directly on the pituitary to negatively regulate FSH beta mRNA levels, and to positively regulate alpha-subunit mRNA levels in the presence of GnRH.     

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

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

Age related changes in follicle stimulating hormone, luteinizing hormone, oestradiol and immunoreactive inhibin in women of reproductive age

OBJECTIVE--In women over the age of 45 years with continuing regular menstrual cycles, follicular phase FSH levels rise without an accompanying change in LH. We determined the effect of increasing age in women with regular cycles on the serum levels of FSH, LH, immunoreactive inhibin, progesterone and oestradiol. DESIGN--Single blood samples were taken during the early follicular phase (days 4-7) and again in the midluteal phase (3-12 days before the next menses) of the menstrual cycle. PATIENTS--Regularly cycling women aged 21-49 years participated in the study (and were grouped into four groups: 20-29, 30-39, 40-44 and 45-49 years in the follicular phase and three groups: 20-29, 30-39 and 40-49 years in the luteal phase. MEASUREMENTS--Serum levels of FSH, LH, oestradiol, progesterone and immunoreactive inhibin were measured from the blood samples obtained. RESULTS--Follicular phase Mean follicular phase levels of immunoreactive inhibin were significantly lower in the 45-49 year age group (P less than 0.05) than in the younger age groups (128 U/l in the 45-49 year age group vs 239, 235 and 207 U/l in the 20-29, 30-39, 40-44 year age groups respectively), while mean FSH levels were significantly higher in the 45-49 year age group (P less than 0.05, 13.0 IU/l in the 45-49, 4.9, 5.5 and 5.2 IU/l in the 20-29, 30-39 and 40-44 year age groups respectively). Mean oestradiol levels in the 45-49 year age group were significantly lower only when compared to age group 30-39 years (P less than 0.05, 130 vs 210 pmol/l). There was no significant difference in oestradiol levels between the 45-49 year age group and the 20-29 and 40-44 year age groups. LH levels did not differ significantly across age groups. There was also a significant negative correlation between serum immunoreactive inhibin and FSH (r = -0.45, P less than 0.05) and between oestradiol and FSH (r = -0.35, P less than 0.05). There was a significant negative relationship between immunoreactive inhibin and age (r = -0.46, P less than 0.05). For every 10-year increase in age, average immunoreactive inhibin decreased by an estimated 49.3 U/l. As age increased, average FSH levels exhibited a two-phase linear increase with the change-point estimated at 42.97 (1.42) (estimate (SE)) years. Prior to 42.97 years, FSH barely changed; after 42.97 years there was a significant (P less than 0.05) increase in FSH as age increased. Oestradiol levels did not change significantly until an estimated 37.9 years of age, but then decreased significantly (P less than 0.05) with increasing age. Luteal phase Levels of FSH, LH, serum immunoreactive inhibin, oestradiol and progesterone fell slowly with increasing age. There was a significant correlation between serum immunoreactive inhibin with progesterone (r = 0.41, P less than 0.05) but there was no correlation between serum immunoreactive inhibin LH or FSH. CONCLUSION--The results are consistent with a role for serum immunoreactive inhibin, in addition to oestradiol, in the regulation of FSH during the follicular phase of the menstrual cycle as a function of increasing age. This is postulated to reflect diminished folliculogenesis as age progresses with the known decline in the numbers of primordial follicles in the ovary as the menopause approaches.     

CHANGES IN THE PITUITARY-TESTICULAR SYSTEM WITH AGE

In order to provide a comprehensive account of pituitary-testicular function in man, 466 subjects, ranging in age from 2 to 101 years, were studied to examine blood levels of the pituitary gonadotrophins (LH and FSH), the sex steroids testosterone and oestradiol, the binding capacity of the sex hormone binding globulin (SHBG), the free testosterone and oestradiol fractions, and the transfer constant for the peripheral conversion of testosterone to oestradiol. The results were compared with clinical indices of testicular size, sexual function and secondary sex hair distribution. Serum LH and FSH were low before puberty, increased in pubertal adolescents to levels somewhat above those of adults and subsequently increased progressively over the age of 40 years. Testosterone levels fell slowly after the age of 40, while there was a slight rise in plasma oestradiol with increasing age. FSH and testosterone showed small seasonal variations in young adult men, the lowest values being seen in winter. SHBG binding capacity was high in two prepubertal boys, fell in adult men, but increased in old age. Free testosterone and oestradiol levels fell in old age. The metabolic clearance rates (MCR) of testosterone and oestradiol also fell in old age, while the conversion of testosterone to oestradiol was increased. Many correlations were observed between various hormonal and clinical measurements. The evidence is consistent with a primary decrease in testicular function over the age of 40 years.     

Endogenous sex hormones in relation to age, sex, lifestyle factors, and chronic diseases in a general population: the Tromsø Study

The role played by endogenous hormones in many diseases makes it important to understand factors influencing their levels. This study examined the distribution of total and free estradiol, FSH, and dehydroepiandrosterone sulfate (DHEAS) by age and sex and associations of these hormones with body mass index (BMI), lifestyle factors, and chronic diseases. Plasma samples taken from 1555 men and 1952 women 25-84 yr of age in 1994-1995 Troms? Study were analyzed in 2001. Total estradiol increased with age among men (P < 0.001), with or without adjustment for BMI and lifestyle factors. FSH increased with age both in men (P < 0.001) as well as pre- (P < 0.001) and postmenopausal women (P = 0.01) after similar adjustment, and DHEAS decreased with age in both sexes (P < 0.001). With increasing BMI, free estradiol increased in men (P = 0.004), total and free estradiol increased in postmenopausal women (P < 0.001), and FSH decreased in men (P = 0.03) and postmenopausal women (P < 0.001). Men with chronic diseases had lower levels of DHEAS, compared with healthy men (P < 0.001). Smokers had higher DHEAS levels than nonsmokers. Further studies are needed to confirm these hormonal changes with age and disease.     

Ovarian age-related responsiveness to human chorionic gonadotropin

Human fertility starts to decline after the age of 30 yr, but the change in ovarian endocrine function, i.e. estrogen biosynthesis, with advancing age is not well understood. To study age-related changes in androgen secretion and ovarian capacity to synthesize/release androgens in response to human chorionic gonadotropin (hCG) stimulation, 44 healthy women (aged 20-44 yr) were investigated. Just before a single im injection of 5000 IU hCG, blood samples for LH, FSH, inhibin B, 17-hydroxyprogesterone (17-OHP), androstenedione (A), testosterone (T), and estradiol (E(2)) assays were collected. Further samples were taken at 24, 48, 72, and 96 h. The responses of 17-OHP, A, and T to hCG, i.e. areas under the curves (AUC; 96 h), correlated negatively with age (17-OHP: r = -0.427; P = 0.004; A: r = -0.266; P = 0.081; T: r = -0.354; P = 0.018). Despite a decreasing capacity of the ovaries to secrete these estrogen precursors, the basal serum levels of E(2) remained unchanged. This may be due to the rise in serum FSH levels observed as early as after the age of 25 yr [25 yr: FSH, 7.7 +/- 0.9 U/liter; P = 0.01]. No correlation was found between age and serum inhibin B levels. In conclusion, ovarian androgen secretion capacity starts to decline as early as before the age of 30 yr. Despite that, circulating E(2) levels remain normal for years, possibly due to compensatory mechanisms, reflected by the gradual rise in serum FSH levels.