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Injectable contraceptives differentially affect the hypothalamic-pituitary-gonadal axis and amenorrhea incidence†.

Alexis J Bick1, Chanel Avenant1, Carole-Keza Capitaine1

  • 1Department of Molecular and Cell Biology, University of Cape Town, Cape Town, Western Cape, South Africa.

Biology of Reproduction
|January 5, 2026
PubMed
Summary

Depot medroxyprogesterone acetate (DMPA-IM) and norethisterone enanthate (NET-EN) hormonal contraceptives affect the hypothalamic-pituitary-ovarian axis differently. DMPA-IM users experienced more amenorrhea due to distinct hormonal profiles compared to NET-EN users.

Keywords:
amenorrheagonadotropin-releasing hormonegonadotropinshypothalamic–pituitary-ovarian axismedroxyprogesterone acetatenorethisteroneovarian steroids

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Area of Science:

  • Endocrinology
  • Reproductive Health
  • Pharmacology

Background:

  • Hormonal contraceptives modulate the hypothalamic-pituitary-ovarian (HPO) axis, but mechanisms and contraceptive-specific differences remain underexplored.
  • Previous trials indicated similar estradiol reduction but more amenorrhea with DMPA-IM versus NET-EN.

Purpose of the Study:

  • To investigate the distinct effects of DMPA-IM and NET-EN on the HPO axis and associated hormonal profiles.
  • To explore potential mechanisms underlying contraceptive-induced amenorrhea.

Main Methods:

  • Secondary analysis of 128 women from a randomized trial comparing DMPA-IM and NET-EN.
  • Analysis of peripheral blood serum for gonadal steroids, progestins, and peptide hormones at baseline and 25 weeks.
  • Assessment of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels.

Main Results:

  • DMPA-IM showed less LH suppression and increased FSH compared to NET-EN, which decreased FSH.
  • Both contraceptives significantly reduced gonadal steroids, with NET-EN causing greater reductions in testosterone and estradiol.
  • Post-menopausal-like hypoestrogenic effects were observed, greater than previously reported, linked to LH reduction.

Conclusions:

  • HPO hormone profiles differ significantly between DMPA-IM and NET-EN users.
  • Mechanisms contributing to amenorrhea likely vary between DMPA-IM and NET-EN, with lower LH/FSH levels correlating with amenorrhea in DMPA-IM users.
  • MPA may have direct pituitary effects, potentially mediated via the glucocorticoid receptor, influencing FSH levels.