Associations of LH and FSH with reproductive hormones depending on each stage of the menopausal transition

doi:10.21203/rs.3.rs-2082820/v1

Introduction: Associations of luteinizing hormone (LH) with androgens during the menopausal transition and associations between follicle-stimulating hormone (FSH) levels and various diseases related to reproductive hormones in postmenopause have received much attention. LH and FSH are also known to be associated with activities of enzymes related to reproductive hormones. We examined the associations of LH and FSH with androgens and estrogens in each stage according to a classification from menopausal transition to postmenopause.

Methods: We divided the 173 subjects into 6 groups according to menstrual regularity and follicle-stimulating hormone level: mid reproductive stage (Group A), late reproductive stage (Group B), early menopausal transition (Group C), late menopausal transition (Group D), very early postmenopause (Group E) and early postmenopause (Group F). Levels of LH, FSH, dehydroepiandrosterone sulfate (DHEAS), estradiol, estrone, testosterone (T), free T, androstenedione and androstenediol were measured.

Results: In Group A, LH showed significant positive correlations with androstenedione and estrone. In Group D, LH was positively associated with T and free T and was negatively associated with estradiol. In Groups B, C, D and F, LH showed significant positive correlations with FSH, and there was a tendency for an association between LH and FSH in Group E. FSH was associated with estradiol but not with estrone in Groups C and D.

Conclusion: The associations of LH and FSH with reproductive hormones were different according to the stage of the menopausal transition. The associations between gonadotrophine levels and androgen levels may be important for metabolism from menopausal transition to postmenopause.

LH

FSH

menopausal transition

androgen

During the menopausal transition, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) produced in the pituitary increase to compensate for the declining estradiol levels due to a decrease in ovarian function. Based on changes in FSH trajectory accelerations and decelerations and rates of change, four menopausal transition stages bounding the final menstrual period and eight epochs in chronological aging from ages of 28 to 60 years have been defined [1]. Also, in women aged 42-52 years, three FSH trajectories over the menopausal transition have been identified [2]. Previous studies have shown that FSH receptors are distributed in various tissues including the bone [3, 4], liver [5] and vessels [6] as well as the ovary. It has been shown that FSH has extragonadal actions and that FSH levels are associated with various diseases and with metabolism in postmenopause [7, 8]. On the other hand, LH receptors are also distributed in not only the ovary but also the adrenal gland [9], brain [10], skin [11] and bladder [12]. It has been reported that an LH level of less than 41 U/L showed a positive correlation with dehydroepiandrosterone sulfate (DHEAS) level in postmenopausal women but not in women during the menopausal transition [13], suggesting that DHEAS production from the adrenal gland may be stimulated by highly elevated LH levels [13]. Although much attention has been focused on the delta-4 steroidogenic pathway that produces cortisol, androstendione and testosterone, longitudinal studies have suggested that the delta-5 steroidogenic pathway that produces DHEA, DHEAS and androstenediol may play a more important role in women’s healthy aging [14, 15]. It has been reported that gonadotropins such as LH and FSH change the activities of enzymes, including cytochrome P450 (CYP) 17A, 3β-hydroxysteroid dehydrogenase (HSD) and 17β-HSD, that act in the delta-4 and delta-5 steroidogenic pathways [16, 17, 18, 19]. During the menopausal transition, increases in LH and FSH levels change the activities of enzymes and might be associated with changes in reproductive hormones.

In 2012, the Stage of Reproductive Aging Workshop (STRAW)+10 staging system was revised. The revised staging system improves the comparability of studies of midlife women and is widely considered as the gold standard for characterizing reproductive aging through menopause [20]. Based on the STRAW staging system, we found associations of androstenediol levels related to the delta-5 steroidogenic pathway with estrogen and androgen in women during the menopausal transition in a previous study by using liquid chromatography mass spectrometry (LC-MS/MS) with high sensitivity and high specificity [21]. Associations of LH with androgens during the menopausal transition have been shown, but there has been no report on the associations between FSH and androgens including androstenediol. The associations of LH and FSH with reproductive hormones related to the adrenal gland may differ according to each stage in the STRAW classification. To our knowledge, there are few data on the associations of gonadotropins such as LH and FSH with androgens and estrogens by classifying menopausal transition in detail. The aim of this study was to determine the associations of LH and FSH with reproductive hormones in each stage of the menopausal transition.

Subjects

We recruited 173 Japanese women for this cross-sectional study from the outpatient clinic of the Department of Obstetrics and Gynecology in Tokushima University Hospital. These women visited a specialized health care outpatient clinic for consultation and for management and treatment of various conditions including decrease in bone mineral density, dyslipidemia and menopausal symptoms. Women who had received hormone therapy in the past year were excluded. At the time of the visit to the outpatient clinic, we obtained information on menstrual frequency and flow or years since the final menstrual period (FMP) and we measured FSH level and determined the stage of menopausal transition. Based on the STRAW staging system [20], we divided the subjects into 6 stages by menstrual regularity and FSH level: 1) women with a regular menstrual cycle (25–35 days per cycle) and normal FSH level (mid reproductive stage, Group A, n=21), 2) women with a regular menstrual cycle and elevated FSH level (>10 mIU/ml) (late reproductive stage, Group B, n=22)，3) women with an irregular menstrual cycle and elevated FSH level (>10 mIU/ml) (early menopausal transition, Group C, n=23), 4) women who had an irregular menstrual cycle in which the interval of amenorrhea was more than 2 months and who had elevated FSH level (late menopausal transition, Group D, n=35), 5) women for whom less than 1 year had passed since menopause (very early postmenopause, Group E, n=30), and 6) women for whom more than 1 year and less than 5 years had passed since menopause (early postmenopause, Group F, n=42). Informed consent for participation in this study was obtained from each woman. The Ethics Committee of Tokushima University Hospital approved the study.

Measurements

Blood in women with menstruation was drawn from 9:00 to 12:00 during a period of 3-7 days after the commencement of menstruation. Blood samples for measurements were obtained by venipuncture and drawn into tubes. They were frozen at -40℃ until used for analysis. Levels of LH, FSH, estradiol and testosterone (T) were measured by a chemiluminescent immunoassay. DHEAS level was measured by a chemiluminescent enzyme immunoassay. Levels of androstenedione and free T were measured by a radioimmunoassay. The intra- and inter-assay coefficients (CVs) for DHEAS, T, free T, estradiol, androstenedione, LH and FSH were less than 10%. Serum androstenediol and estrone concentrations were measured by using LC-MS/MS, and the measurements were described in our previous report (21). The intra- and inter-assay CVs for androstenedione measurements were 2.3-2.9% and 4.4-6.3%, respectively. The intra- and inter-assay CVs for estrone measurements were 2.0-2.3% and 3.0-3.2%, respectively. The sensitivity of the assay was 0.01 ng/ml for androstenediol and estrone.

Statistical analysis

All statistical analyses were performed by using SPSS statics version 20.0 (IBM, Armonk, New York). Data are presented as medians with 25th and 75th ranges and LH/FSH ratio is shown as a mean. The Kruskal-Wallis rank test was used to compare differences between different menopausal stages, and Bonferroni adjustment was used for a multiple comparison test. Correlations between variables were assessed by Spearman’s rank correlation analysis.

Background characteristics of the subjects are shown in Table 1. Median body mass index (BMI) ranged from 20.1 to 22.5 kg/㎡, and there was no significant difference in BMI among the groups. BMI in one woman was more than 30.0 kg/㎡ (Table 1).

Changes in LH and FSH levels during the menopausal transition

Changes in LH and FSH levels during the menopausal transition are shown in Figure 1. Both LH and FSH levels were significantly increased in Groups D, E and F compared to those in Group A. In addition, LH level tended to be increased in Group C compared to that in Group A (p=0.062)

FSH level continued to increase after Group D, but LH level reached a plateau at Group E (Fig.１A and B). There was no significant difference in the LH/FSH ratio among the 6 groups (Table 1)

The box indicates values from the 25th percentile to the 75th percentile. The vertical line in the box indicates the median and the cross mark indicates the mean. Vertical lines represent minimum and maximum values. * p <0.05 vs Group A. ** p=0.06 vs Group A

Group A: mid reproductive stage, Group B: late reproductive stage, Group C: early menopausal transition, Group D: late menopausal transition, Group E: very early post menopause, Group F: early postmenopause.

Correlations of LH with reproductive hormones

As can be seen in Table 2, in Group A, LH level showed significant and positive correlations with levels of androstenedione and estrone (r=0.747, p=0.003; r=0.782, p=0.038). In Group D, LH level was positively associated with levels of T and free T (r=0.356, p=0.036 and r=0.414, p=0.041, respectively) and was negatively associated with estradiol level (r=-0.484, p=0.003). Positive associations between LH and FSH were found in Groups B, C, D and F (r=0.713, p<0.001; r=0.776, p<0.001; r=0.692, p<0.001; r=0.688, p<0.001), and a tendency for a positive correlation between LH and FSH was found in Group E (r=0.358, p=0.052) (Table 2).

Correlations of FSH with reproductive hormones

In Groups C and D, FSH level showed a significant and negative association with estradiol level (r=-0.432, p=0.039 and r=-0.720, p<0.001, respectively) but not with estrone level. FSH level was not associated with testosterone, DHEAS, androstenediol or androstenedione (Table 3).

In the present study, we found that the associations of LH and FSH with reproductive hormones differ according to stages of the menopausal transition.

Women in Group A had a normal range of FSH levels. However, the ages of women in Group A ranged from 41.6 to 46.5 years and gradually approached the age for menopause. The fact that the delta-4 pathway for synthesis of androstenedione and estrone acts well along with actions of 17β-HSD and 3β-HSD in women in that age range is thought to be the reason for the significant correlations of LH level with estrone and androstenedione levels in Group A. In women in Group A, the delta-4 pathway in the ovary may have been maintained due to a balance between LH and FSH.

In Group B, in which ovarian function had begun to decrease, there was no significant association of LH level with androstenedione or estrone level. Through an increase in FSH level, a relationship in which the balance between LH and FSH was maintained in Group A was attenuated, and the shift was beginning toward the delta-5 pathway. In addition, stimulation of DHEAS production by augmentation of CYP17A1 activity due to an increase in LH may be the reason for the disappearance of correlations of LH with androstenedione and estrone. A correlation between LH and FSH was found with increasing FSH level.

In several studies, fibrosis in the stroma was observed in the ovary and associations between LH and androgens were found in women approaching menopause. Reproductive age-associated fibrosis was found in the stroma of ovaries in mice and humans [22, 23]. Matt et al. reported that alterations in hypothalamic-pituitary function such as a prolonged interpulse interval of LH and increased LH pulse width were found in middle-aged women with a mean age of 42.6 years [24]. Thompson et al. found in a study using ovarian tumor cells that androgens are synthesized and secreted by the human ovary and that the primary source of androgens is the stromal cell compartment in the menopausal ovary [25]. A tripartile relationship among increase in LH, increase in androgens and fibrosis in the stroma in the ovary was also found in women with polycystic ovary syndrome (PCOS) [26]. Wickenheisser et al. reported that CYP17 gene expression increased for biosynthesis of androgens in theca interna cells in women with PCOS [17]. Moran et al. reported that women with PCOS who had an excess of adrenal androgen had significantly higher activity of CYP17 than that in women with PCOS who did not have an excess of adrenal androgen [16]. Thus, stimulation of DHEAS production by activation of CYP17A1 induces a hyperandrogenic state in women with PCOS [16, 17]. The results of those previous studies suggest that there are changes such as fibrosis in the ovarian stroma and transient increases in LH and androgens with aging. In Group C, production of androgen was started by the effect of increased LH level and a transition from the delta-4 pathway to the delta-5 pathway was proceeding. Negative correlations between FSH and estradiol were found to be significant in Group C and remarkable in Group D. When women enter into the periods of Group C and Group D, which indicate menopausal transition, the negative correlation between estradiol and FSH might become stronger due to the remarkable decline in estradiol level.

Murayama et al. reported that theca cells pretreated with a high concentration of LH showed increased CYP17 gene expression [18]. Oktem et al. reported that FSH up-regulated the mRNA expression of 17β-HSD and 3β-HSD in granulosa cells [19]. Due to an increase in LH in the late menopausal transition, CYP17A1 activity increases via LH receptors in the adrenal gland and the conversion from pregnenolone to DHEAS is stimulated. DHEAS level tended to increase, but the difference was not statistically significant (p = 0.062), in the present study. However, in a previous study, a transient increase in DHEAS was found in the late menopausal transition [27]. In the present study, LH was significantly associated with total T and free T in Group D (late menopausal transition). As well as DHEAS production in response to LH stimulation, conversion to T by stimulation of 17β-HSD activity via FSH increase is considered to be involved in this significant correlation. The positive relationships between level of LH and levels of androgens such as T, free T and DHEAS may indicate that the delta-5 pathway is the main pathway in Group D. In the late menopausal transition, LH and FSH may act cooperatively on enzyme activities and stimulate reproductive hormone production.

In Groups B, C, D and F, there were positive and significant associations between LH and FSH, but there was only a tendency for a correlation between LH and FSH in Group E. In the present study, in Group F, FSH level continued to increase, although LH level showed a plateau (Fig. 1). The time difference in hormonal changes in which FSH reached a plateau later than LH might be involved in the weak correlation between LH and FSH in Group E. In addition, in Group E, the correlations of LH with T and free T shown in Group D disappeared. The reason is conversion from T to estradiol by an increase in aromatase through continuation of the increase in FSH, and this phenomenon was maintained in Group F. During the menopausal transition, FSH may regulate androgen levels for prevention of an excessive increase in androgen levels.

In postmenopausal women, associations of FSH levels with the development of various diseases and with metabolism have been reported [28, 29, 30]. A high FSH level was shown to be associated with prevalence of vasomotor symptoms [31] and an increase in low-density lipoprotein cholesterol [5], and a low FSH level was shown to be associated with non-alcoholic fatty liver disease [32] and diabetes mellitus [30]. Serum FSH levels have been shown to be correlated with the rate of bone loss in perimenopausal women [33] and in older women [34]. However, the associations that were investigated in those studies were for FSH levels, not LH levels, in postmenopausal women. The associations of FSH levels with lipid metabolism, carbohydrate metabolism and vascular function in postmenopause may be affected by the increase in androgen levels due to an increase in LH during the menopausal transition. Combined studies on LH levels and FSH levels from menopausal transition to postmenopause may be valuable.

Fibrosis in the stroma in the ovary and increases in LH and androstenedione occur in women with aging. Stimulation of 17β-HSD activity due to an increase in FSH might be regulated so as to prevent an excessive increase in androgen levels, particularly in postmenopausal women with high FSH levels. We did not examine the associations of LH and FSH with lipid metabolism and insulin resistance in each stage of the menopausal transition. Studies on associations of LH with the development of various diseases and with metabolism should be carried out not only for women in postmenopause but also for women during the menopausal transition.

There are some limitations in this study. The sample size in the present study might be insufficient for a generalization for all Japanese women. Further study with a large sample size is needed. This study was a cross-sectional study. Thus, a causal relationship needs to be clarified in a longitudinal study. In addition, measurements of various enzymes related to the production of hormones may be important to clarify individual differences in enzyme activities. In the present study, total circulating reproductive hormones were measured, and we could not separate ovary-derived reproductive hormones and adrenal gland-derived reproductive hormones.

The associations of LH and FSH with reproductive hormones are different depending on the stage of the menopausal transition. The associations between gonadotropin levels and androgen levels may be important for metabolism from menopausal transition to postmenopause.

Statements and Declarations

Ethics declarations

Conflicts of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

The study protocol was developed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Tokushima University Hospital.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Contributors

Takako Kawakita participated in research conception and design, data acquisition, data analysis and interpretation, drafting, and critical revision of the critical intellectual content.

Toshiyuki Yasui participated in the conception and design of the study, data acquisition, data analysis and interpretation, and critical revision of the intellectual content of the paper.

Kanako Yoshida participated in data analysis and interpretation, as well as critical revision of key intellectual content.

Sumika Matsui participated in the conception and design of the study, data acquisition, data analysis and interpretation, and critical revision of the critical intellectual content.

Takeshi Iwasa participated in data analysis and interpretation, as well as critical revision of key intellectual content.

All authors have seen and approved the final version, and no one else has made a substantive contribution to the paper.

Acknowledgement

We would like to express our deep gratitude to the subjects who participated in this study.

Ethical approval

Informed consent was obtained from all participants before participating in the study. The study protocol was developed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Tokushima University Hospital.

Declaration of competing interest

The authors declare that they have no competing interest.

Provenance and peer review

This article was not commissioned and was externally peer reviewed.

Funding

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

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Table 1. Clinical characteristics of the subjects

		Group						P value
		A	B	C	D	E	F	P value
Number		21	22	23	35	30	42
Age	years	43.5 41.50-46.50	47 44.50-49.00	47* 46.00-49.00	49* 46.50-50.50	51* 49.50-53.00	53* 51.75-54.00	<0.001
Height	cm	155.0 152.25-157.00	158.0 154.00-160.85	160.4 158.93-163.00	158.7 156.63-160.00	158.0 154.00-160.00	156.5 155.00-159.05	0.189
Weight	kg	50.1 47.70-56.25	55.9 50.5-57.65	56.0 52.65-58.53	59.0 52.00-61.20	52.0 49.40-57.40	53.1 50.00-57.15	0.182
BMI	kg/cm²	20.1 19.50-21.50	21.4 20.00-23.55	21.8 20.51-23.13	22.5 20.31-25.00	21.9 20.09-22.79	21.7 20.30-23.53	0.379
LH	mIU/ml	3.7 2.83- 5.90	7.2 4.05-13.28	8.8 7.7- 26.3	30.05* 17.48- 35.78	33.30* 20.80- 43.90	30.55* 23.5- 38.48	<0.001
FSH	mIU/ml	5.6 4.80- 8.00	14.05 11.15- 35.18	23.9 13.5- 42.9	56.95* 30.55- 87.35	93.40* 70.70- 110.0	95.85* 71.43- 123.70	<0.001

Group A: mid reproductive stage, Group B: late reproductive stage, Group C: early menopausal transition, Group D: late menopausal transition, Group E: very early post menopause, Group F: early postmenopause. Age, height, weight, BMI, LH and FSH are shown as medians. LH/FSH ratio is shown as a mean. LH: luteinizing hormone, FSH: follicle-stimulating hormone.

Table 2. Correlations of LH with reproductive hormones

Group A

Group B

Group C

Group D

Group E

Group F

testosterone

R=0.223

P=0.331

R=－0.033

P=0.883

R=－0.037

P=0.867

R=0.356

P=0.036

R=－0.004

P=0.985

R=－0.004

P=0.978

Free testosterone

R=0.233

P=0.309

R=0.216

P=0.335

R=－0.180

P=0.410

R=0.414

P=0.041

R=－0.205

P=0.277

R=－0.153

P=0.332

DHEAS

R=0.235

P=0.304

R=－0.051

P=0.827

R=0.234

P=0.283

R=0.295

P=0.090

R=0.136

P=0.480

R=0.076

P=0.632

androstenedione

R=0.747

P=0.003

R=0.000

P=1.000

R=0.473

P=0.142

R=－0.010

P=0.970

R=0.024

P=0.955

R=0.000

P=1.000

androstenediol

R=－0.146

P=0.688

R=－0.071

P=0.867

R=0.052

P=0.813

R=0.250

P=0.516

R=－0.204

P=0.279

R=－0.018

P=0.907

estradiol

R=0.427

P=0.053

R=0.166

P=0.459

R=0.300

P=0.433

R=－0.484

P=0.003

R=－0.214

P=0.645

R=0.533

P=0.139

estrone

R=0.782

P=0.038

R=0.048

P=0.911

R=－0.217

P=0.576

R=－0.095

P=0.823

R=0.501

P=0.116

R=－0.009

P=0.979

FSH

R=0.233

P=0.309

R=0.713

P=0.000

R=0.776

P=0.000

R=0.692

P=0.000

R=0.358

P=0.052

R=0.688

P=0.000

Cortisol

R=0.408

P=0.067

R=－0.311

P=0.170

R=－0.057

P=0.797

R=0.034

P=0.849

R=0.203

P=0.290

R=－0.040

P=0.804

Spearman correlation coefficients were used to evaluate the correlations of LH with reproductive hormones for each group.

Group A: mid reproductive stage, Group B: late reproductive stage, Group C: early menopausal transition, Group D: late menopausal transition, Group E: very early post menopause, Group F: early postmenopause.

DHEAS: dehydroepiandrosterone sulfate, T: testosterone FSH: follicle-stimulating hormone.

Table 3. Correlations of FSH with reproductive hormones

Stage

Group A

Group B

Group C

Group D

Group E

Group F

testosterone

R=－0.085

P=0.715

R=－0.163

P=0.469

R=－0.059

P=0.789

R=0.145

P=0.407

R=－0.159

P=0.402

R=－0.030

P=0.853

Free testosterone

R=－0.021

P=0.929

R=0.120

P=0.595

R=－0.079

P=0.719

R=0.135

P=0.438

R=－0.334

P=0.071

R=－0.180

P=0.253

DHEAS

R=0.067

P=0.772

R＝－0.065

P= 0.780

R=0.354

P=0.098

R=0.302

P=0.082

R=－0.159

P=0.411

R=0.076

P=0.632

androstenedione

R=－0.307

P=0.308

R=0.013

P=0.965

R=0.227

P=0.502

R=－0.216

P=0.405

R=0.048

P=0.911

R=－0.393

P=0.383

androstenediol

R=0.129

P=0.723

R＝－0.024

P=0.955

R=－0.275

P=0.509

R=－0.233

P=0.546

R=－0.500

P=0.253

R=0.000

P=1.000

estradiol

R=－0.318

P=0.160

R=－0.222

P=0.321

R=－0.432

P=0.039

R=－0.720

P=0.000

R=－0.158

P=0.406

R=0.015

P=0.925

estrone

R=－0.309

P=0.500

R=－0.167

P=0.693

R=－0.600

P=0.088

R=－0.452

P=0.260

R=0.209

P=0.537

R=0.300

P=0.370

LH

R=0.233

P=0.309

R=0.713

P＝0.000

R=0.776

P=0.000

R=0.692

P=0.000

R=0.358

P=0.052

R=0.688

P=0.000

Cortisol

R=0.026

P=0.911

R=－0.268

P=0.240

R=0.094

P=0.670

R=0.009

P=0.960

R=0.018

P=0.926

R=0.003

P=0.983

Spearman correlation coefficients were used to evaluate the correlations of FSH with reproductive hormones and cortisol for each group.

Group A: mid reproductive stage, Group B: late reproductive stage, Group C: early menopausal transition, Group D: late menopausal transition, Group E: very early post menopause, Group F: early postmenopause.

DHEAS: dehydroepiandrosterone sulfate, T: testosterone, LH: luteinizing hormone.

No competing interests reported.

Associations of LH and FSH with reproductive hormones depending on each stage of the menopausal transition

Archived Versions:

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Abstract

Figures

Introduction

Subjects And Methods

Results

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Archived Versions:

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