Desogestrel

證據等級: L5

預測適應症: 10 個

Desogestrel: From Oral Contraception to Amenorrhea

One-Sentence Summary

Desogestrel is a third-generation synthetic progestogen used in combined and progestogen-only oral contraceptive formulations for the prevention of pregnancy. The TxGNN model predicts it may be relevant to the management of Amenorrhea, with 2 clinical trials and 16 publications currently supporting this direction.

⚠️ Critical Clinical Note: Desogestrel’s progestogen-only pill formulation (75 µg/day) is itself a well-established cause of amenorrhea in approximately 50% of users. The repurposing prediction must be interpreted carefully: the therapeutic direction depends entirely on clinical context, underlying pathophysiology, and the specific formulation used.

Quick Overview

Item	Content
Original Indication	Oral contraception (no formal registration found in Denmark; globally used in combined OC and progestogen-only pill formulations)
Predicted New Indication	Amenorrhea
TxGNN Prediction Score	99.96%
Evidence Level	L3
Denmark Market Status	Not marketed
Number of Marketing Authorisations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Desogestrel is a prodrug metabolised to its pharmacologically active form, etonogestrel (3-keto-desogestrel). Etonogestrel binds selectively to the progesterone receptor and modulates the hypothalamic-pituitary-ovarian (HPO) axis primarily by suppressing the mid-cycle LH surge, thereby inhibiting ovulation. Among third-generation progestogens, desogestrel is notable for its markedly low androgenic activity compared to older agents such as levonorgestrel.

The mechanistic bridge to amenorrhea management operates across two distinct clinical contexts. In PCOS-associated amenorrhea driven by hyperandrogenic anovulation, the low androgenic activity of etonogestrel may competitively reduce androgen-receptor stimulation at the ovarian and peripheral level, potentially supporting cycle normalisation. In functional hypothalamic amenorrhea — for example, in athletes with Relative Energy Deficiency in Sport (RED-S / Female Athlete Triad) — exogenous progestogen supplementation may provide endometrial protection and contribute to cycle restoration, as supported by the Phase 3 trial NCT00946192.

A fundamental bidirectionality, however, challenges the repurposing rationale directly: the progestogen-only pill formulation of desogestrel (75 µg/day) induces amenorrhea in approximately 50% of users through sustained suppression of follicular development and consequent hypoestrogenism. This means desogestrel can both cause and — in other formulations or contexts — potentially treat amenorrhea. The net clinical direction is not intrinsic to the molecule but depends entirely on the subtype of amenorrhea, the formulation chosen, and the patient population.

Detailed mechanism of action data from DrugBank was not available at the time of report generation. The above mechanistic reasoning is based on published pharmacodynamic literature.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00946192	Phase 3	Completed	121	Investigates fat-mediated modulation of reproductive and endocrine function in young athletes, directly addressing exercise-associated amenorrhea (FAT/RED-S). Compares transdermal vs. oral estrogen for bone density restoration in amenorrheic, estrogen-deficient adolescent athletes. Provides the most directly relevant clinical context for progestogen use in functional hypothalamic amenorrhea, though desogestrel is not the primary intervention.
NCT01588873	Phase 4	Unknown	42	Compares oral combined OC versus vaginal ring over 59 weeks on hormonal, inflammatory, and metabolic parameters in PCOS women of reproductive age. Amenorrhea is not the primary endpoint; the study is relevant as an indirect source on desogestrel-containing COC effects in the PCOS-related hyperandrogenic anovulation context. Small sample and unknown status limit confidence.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
35261299	2022	Observational Study	Gynecological Endocrinology	Directly compares bleeding profiles of drospirenone-only pill (4 mg) versus desogestrel 0.075 mg in women with cardiovascular risk factors over nine cycles. Confirms amenorrhea as a key adverse outcome of the desogestrel POP, with poor cycle control potentially impairing acceptability and compliance — directly relevant to the bidirectionality concern.
8218004	1993	RCT	British Journal of Obstetrics and Gynaecology	Randomised comparison of two formulations both containing desogestrel 150 µg combined with either 20 µg (Mercilon) or 30 µg (Marvelon/Desolett) ethinyl oestradiol; evaluates reliability, cycle control, and side effect profile — foundational data for understanding desogestrel’s contribution to cycle regulation.
18843653	2008	Cochrane Systematic Review	Cochrane Database of Systematic Reviews	Systematic review of 20 µg vs. >20 µg estrogen combined OC formulations, including desogestrel-containing pills; assesses contraceptive effectiveness and bleeding pattern changes. Relevant as the highest-tier evidence on cycle outcomes with desogestrel COC combinations.
21249657	2011	Cochrane Systematic Review	Cochrane Database of Systematic Reviews	Updated Cochrane review (2011 version) of low-dose estrogen COC formulations; confirms prior findings on bleeding patterns and cycle control outcomes. Directly relevant to the amenorrhea risk-benefit analysis for desogestrel-containing preparations.
11725730	2001	Clinical Study	The Journal of Reproductive Medicine	Evaluates bone mineral density in young women with hypothalamic oligoamenorrhoea treated with oral contraceptives of varying EE dose. Directly relevant to hypothalamic amenorrhoea management with progestogen-containing preparations and the protective role of OCs in this context.
3161265	1985	Pharmacodynamic Study	Acta Obstetricia et Gynecologica Scandinavica	Evaluates the androgenicity of progestogens with specific focus on desogestrel using radioimmunoassay; contextualises its low androgenic profile in relation to PCO syndrome, a condition characterised by amenorrhoea, hirsutism, and acne. Foundational mechanistic evidence.
23221134	2012	Clinical Study	Georgian Medical News	Studies central-genesis dysfunctional menstrual disorders including amenorrhoea and oligomenorrhoea in 159 infertile women based on EEG-guided classification; compares pathogenetic management vs. standard hormone therapy. Provides context for progestogen-based treatment of central amenorrhoea.
8447356	1993	Observational Study	American Journal of Obstetrics and Gynecology	Comprehensive tolerability profile of desogestrel/ethinyl oestradiol combined OC; documents non-contraceptive health benefits and cycle-related effects including impact on dysmenorrhoea and endometriosis — contextually relevant to cycle disorder management.
1436906	1992	Narrative Review	Obstetrical & Gynecological Survey	Reviews third-generation progestins desogestrel, gestodene, and norgestimate; covers chemistry, selective progestational activity, and reduced androgenicity — provides the pharmacological rationale for using desogestrel in androgen-driven hormonal cycle disorders.
8324604	1993	Review	British Medical Bulletin	Reviews safety and efficacy of combined OCs for an estimated 60 million users worldwide; covers screening, monitoring, and cycle control considerations. Provides broad epidemiological context for desogestrel-containing preparations and menstrual cycle effects.

Safety Considerations

Please refer to the approved Summary of Product Characteristics (SmPC) for safety information.

Conclusion and Next Steps

Decision: Hold

Rationale: The TxGNN prediction for Desogestrel in amenorrhea carries a fundamental pharmacological paradox: the progestogen-only pill formulation of desogestrel is a well-established inducer of amenorrhea in ~50% of users, meaning the drug can cause the very condition it is predicted to treat. The available evidence is Level L3 (observational studies and systematic reviews), none of which directly tests desogestrel as a therapeutic agent for amenorrhea; rather, amenorrhea appears predominantly as a side effect or secondary outcome. Combined with the absence of any Denmark marketing authorisation, this indication requires substantially more targeted investigation before proceeding.

To proceed, the following is needed:

Precise definition of the amenorrhea subtype to be addressed (PCOS-related hyperandrogenic anovulation, functional hypothalamic amenorrhoea, or secondary amenorrhoea of another aetiology) — the mechanistic rationale and evidence base differ substantially between subtypes
Retrieval of the full SmPC (including contraindications and warnings) from the Danish Medicines Agency (Lægemiddelstyrelsen) or EMA to complete the safety evaluation; the current data gap here is classified as blocking
Mechanism of action data from DrugBank to formally confirm the HPO axis modulation pathway
Clarification of whether any existing combined OC formulations containing desogestrel already hold a marketing authorisation in Denmark (e.g., via EMA centralised procedure), which would substantially alter the regulatory pathway for this repurposing
A dedicated prospective proof-of-concept study testing a combined OC formulation of desogestrel — not the progestogen-only pill — in a clearly defined amenorrhea population, with cycle restoration as the primary endpoint
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.