Genetic evidence that lower circulating FSH levels lengthen menstrual cycle, increase age at menopause and impact female reproductive health
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Abstract
STUDY QUESTION: How does a genetic variant in the FSHB promoter, known to alter FSH levels, impact female reproductive health? SUMMARY ANSWER: The T allele of the FSHB promoter polymorphism (rs10835638; c.-211G>T) results in longer menstrual cycles and later menopause and, while having detrimental effects on fertility, is protective against endometriosis. WHAT IS KNOWN ALREADY: The FSHB promoter polymorphism (rs10835638; c.-211G>T) affects levels of FSHB transcription and, as a result, circulating levels of FSH. FSH is required for normal fertility and genetic variants at the FSHB locus are associated with age at menopause and polycystic ovary syndrome (PCOS). STUDY DESIGN, SIZE, DURATION: We used cross-sectional data from the UK Biobank to look at associations between the FSHB promoter polymorphism and reproductive traits, and performed a genome-wide association study (GWAS) for length of menstrual cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included white British individuals aged 40-69 years in 2006-2010, in the May 2015 release of genetic data from UK Biobank. We tested the FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; c.-211G>T) for associations with 29, mainly female, reproductive phenotypes in up to 63 350 women and 56 608 men. We conducted a GWAS in 9534 individuals to identify genetic variants associated with length of menstrual cycle. MAIN RESULTS AND THE ROLE OF CHANCE: The FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; MAF 0.16) was associated with longer menstrual cycles [0.16 SD (c. 1 day) per minor allele; 95% confidence interval (CI) 0.12-0.20; P = 6 × 10(-16)], later age at menopause (0.13 years per minor allele; 95% CI 0.04-0.22; P = 5.7 × 10(-3)), greater female nulliparity [odds ratio (OR) = 1.06; 95% CI 1.02-1.11; P = 4.8 × 10(-3)] and lower risk of endometriosis (OR = 0.79; 95% CI 0.69-0.90; P = 4.1 × 10(-4)). The FSH-lowering T allele was not associated with other female reproductive illnesses or conditions in our study and we did not replicate associations with male infertility or PCOS. In the GWAS for menstrual cycle length, only variants near the FSHB gene reached genome-wide significance (P < 5 × 10(-9)). LIMITATIONS, REASONS FOR CAUTION: The data included might be affected by recall bias. Cycle length was not available for 25% of women still cycling (1% did not answer, 6% did not know and for 18% cycle length was recorded as 'irregular'). Women with a cycle length recorded were aged over 40 and were approaching menopause; however, we did not find evidence that this affected the results. Many of the groups with illnesses had relatively small sample sizes and so the study may have been under-powered to detect an effect. WIDER IMPLICATIONS OF THE FINDINGS: We found a strong novel association between a genetic variant that lowers FSH levels and longer menstrual cycles, at a locus previously robustly associated with age at menopause. The variant was also associated with nulliparity and endometriosis risk. These findings should now be verified in a second independent group of patients. We conclude that lifetime differences in circulating levels of FSH between individuals can influence menstrual cycle length and a range of reproductive outcomes, including menopause timing, infertility, endometriosis and PCOS. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: Not applicable.
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The relationship that increasing VFSH shortens the menstrual cycle period is consistent with findings that lower circulating FSH levels lengthen the menstrual cycle.
“This relationship is consistent with findings that suggest that lower circulating FSH levels lengthen the menstrual cycle [57].”
From A Survey of Mathematical Modeling of Hormonal Contraception and the Menstrual Cycle (2024) · cites this paper as [57]
The allele(s) associated with increased risk of endometriosis are also associated with shorter menstrual cycles, earlier age at menopause, increased dizygotic twinning and polycystic ovarian syndrome.
“The allele(s) associated with increased risk of endometriosis are also associated with shorter menstrual cycles, earlier age at menopause, increased dizygotic twinning and polycystic ovarian syndrome24454748.”
From Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism (2017) · cites this paper as [45]
Nominal evidence for association between endometriosis and SNPs upstream of FSHB was recently reported in independent samples from the UK Biobank, providing strong support for this result.
“Nominal evidence for association between endometriosis and SNPs upstream of FSHB was recently reported in independent samples from the UK Biobank providing strong support for this result45.”
From Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism (2017) · cites this paper as [45]
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- Authors
- Ruth, K. S., Beaumont, R. N., Tyrrell, J., Jones, S. E., Tuke, M. A., Yaghootkar, H., Wood, A. R., Freathy, R. M., Weedon, M. N., Frayling, T. M., & Murray, A.
- Affiliations
- University of Exeter (GB)
- Corresponding author
- Murray, Anna
- ORCID
- Venue
- Human Reproduction
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-01-04
- Volume
- 31
- Issue
- 2
- Pages
- 473-481
- ISSN
- 0268-1161 (ISSN-L)
- 1460-2350
- PMC
- PMC4716809
- OpenAlex
- W2257508508
- Cited by
- 70
- References
- 57
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 8 · 2023: 6 · 2022: 9 · 2021: 11 · 2020: 5 · 2019: 5 · 2018: 9 · 2017: 4 · 2016: 4
- FWCI
- 9.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Human Reproduction (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Figshare (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Open Research Exeter (University of Exeter) (submittedVersion, cc-by)
- Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (093707, 104150/Z/14/Z, 104150, WT097835MF, 323195)
- Diabetes Research and Wellness Foundation
- Medical Research Council (MR/M005070/1, WT097835MF)
- European Regional Development Fund
- FP7 Ideas: European Research Council (323195)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Keywords
- follicle-stimulating hormone, menstrual cycle length, age at menopause, women's reproductive health, endometriosis, nulliparity, fertility, polycystic ovary syndrome, genetic variants, FSH levels, women's health, UK Biobank, genome-wide association study
- MeSH terms
- Adult, Aged, Endometriosis, Female, Follicle Stimulating Hormone, Genetic Markers, Humans, Infertility, Female, Male, Menopause, Menstrual Cycle, Middle Aged, Promoter Regions, Genetic, Linear Models, Odds Ratio, Polymorphism, Single Nucleotide, Follicle Stimulating Hormone, beta Subunit, Genetic Association Studies, Reproductive Health
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