Medroxyprogesterone Acetate

Medroxyprogesterone acetate (MPA) is a synthetic progestogen derived from progesterone. Structurally it is the 17α-acetate ester of medroxyprogesterone, carrying a 6α-methyl substitution on the pregnane steroid backbone. These modifications — the 6α-methyl group and the 17α-acetoxy moiety — substantially increase metabolic stability relative to native progesterone, conferring superior oral bioavailability and a prolonged duration of action, particularly in parenteral depot formulations.

MPA is a potent, selective progesterone receptor (PR) agonist. It does not bind sex hormone-binding globulin (SHBG), which distinguishes it from some other progestins. While MPA exhibits weak androgenic activity, it is largely devoid of significant oestrogenic action at therapeutic doses. At high doses, it also demonstrates glucocorticoid receptor cross-reactivity, explaining the Cushingoid features observed in oncology dosing regimens.

It is classified under the hormonal agents — progestogens — and is used across a broad spectrum of gynaecological, oncological, and endocrinological indications.

MPA acts as a potent full agonist at the progesterone receptor (PR), with approximately 100-fold higher binding affinity and transactivation potency compared to endogenous progesterone. This explains why oral doses of just 10 mg/day can suppress ovulation — a task that would require 300 mg/day of exogenous progesterone.

Endometrial Effects

When adequate endogenous oestrogen is present, MPA transforms proliferative endometrium into secretory endometrium. This is the basis for its utility in treating dysfunctional uterine bleeding and for providing endometrial protection in women receiving unopposed oestrogen as HRT.

Hypothalamic–Pituitary Axis Suppression

MPA binds progesterone receptors in the hypothalamus and anterior pituitary, suppressing GnRH secretion and consequently reducing LH and FSH release. This effect is dose- and route-dependent:

• Parenteral high-dose MPA (e.g., 150 mg IM): Reliably inhibits follicular maturation and ovulation — the basis for its contraceptive action.
• Standard oral doses: Do not reliably suppress ovulation. This is a clinically critical point when counselling patients on contraception.

Antiproliferative Effects

MPA inhibits gonadotrophin production and has antiproliferative effects on endometrial tissue. At high doses used in oncology, it induces p53-dependent apoptosis in cancer cell lines and reduces nuclear oestrogen receptor expression and DNA synthesis in endometrial epithelial cells.

Other Receptor Activities

• Androgenic: Weak androgenic activity may contribute to acne and hair loss as adverse effects.
• Glucocorticoid: At high (oncology) doses, cross-reactivity with glucocorticoid receptors produces Cushingoid features — moon facies, fluid retention, glucose intolerance.
• PGRMC1 (membrane PR component-1): MPA weakly stimulates MCF-7 breast cancer cell proliferation via PGRMC1 in vitro, independent of classical PRs. This in vitro observation may partly explain the breast cancer signal observed in the WHI CE/MPA combination study, though the in vivo clinical relevance remains under investigation.

Standard-Dose Oral (2.5–10 mg tablets)

• Secondary amenorrhoea due to hormonal imbalance (excluding organic causes such as fibroids or uterine cancer)
• Abnormal uterine bleeding due to ovulatory dysfunction
• Prevention of endometrial hyperplasia in postmenopausal women receiving unopposed oestrogen HRT (intact uterus)
• Endometriosis — symptom management including dysmenorrhoea and dyspareunia
• Polycystic ovary syndrome (PCOS) — induction of withdrawal bleeding in oligomenorrhoeic or anovulatory women
• Hot flushes associated with androgen deprivation therapy for prostate cancer

Injectable Formulations

• IM 150 mg/mL: Contraception; adjunctive/palliative therapy for inoperable, recurrent, or metastatic endometrial carcinoma (400 mg/mL formulation)
• SC 104 mg/0.65 mL: Contraception; pain management in endometriosis

High-Dose Oral (100–400 mg tablets)

Reserved exclusively for certain oncological indications. Not within the scope of this standard-dose monograph — specialist oncology guidance should be followed.

• Male hypersexuality / paraphilia: High-dose IM MPA has been used for pharmacological libido suppression — a controversial application with significant ethical considerations.
• Preterm birth prevention: Limited evidence for risk reduction in selected high-risk pregnancies; largely superseded by 17-hydroxyprogesterone caproate in most guidelines.
• Progestin-primed ovarian stimulation (PPOS) in ART: Increasingly used as part of IVF stimulation protocols to prevent premature LH surges; MPA co-administered with gonadotrophins during controlled ovarian stimulation.
• Appetite stimulation and cancer cachexia: Related progestin megestrol acetate is more commonly used; MPA occasionally substituted.
• Atypical endometrial hyperplasia / early endometrial cancer (fertility-sparing): MPA 500 mg/day — specialist oncology context only.

Inactive excipients (oral tablets): Typically include crospovidone, lactose monohydrate, magnesium stearate, methylcellulose, pregelatinised corn starch, and sodium lauryl sulfate. Clinicians should verify excipient content per product-specific SmPC — particularly for patients with lactose intolerance.

Administration Notes

• Tablets: Swallow whole with water. May be taken with or without food (though food improves absorption).
• Sublingual administration of tablets is pharmacologically feasible but not routinely recommended.
• IM injections: Administer to gluteal or deltoid region. Vigorously shake suspension immediately before use. Never dilute, never administer IV.
• SC injections: Administer to anterior thigh or abdomen at 45°. Pull skin away from body before injecting. Press lightly — do not rub post-injection.
• If more than 13 weeks have elapsed since the last injectable dose, exclude pregnancy before re-administering.
• Duration of therapy is indication-dependent. Most gynaecological oral courses run 2–3 months. Injectable contraception requires ongoing q13-week scheduling.

Absorption

Distribution

Metabolism

MPA is extensively metabolised in the liver, primarily via CYP3A4-mediated hydroxylation at positions C6β, C21, C2β, and C1β. Additional metabolic routes include 3- and 5-dihydro and 3,5-tetrahydro metabolite formation, as well as conjugation reactions. The 6α-methyl and 17α-acetoxy modifications make MPA more resistant to first-pass metabolism than progesterone, accounting for its superior oral efficacy.

No formal DDI studies with specific CYP3A4 inducers or inhibitors have been conducted for MPA, though CYP3A4 inducers are known to reduce MPA plasma concentrations clinically.

Elimination

• Endometrial transformation: Converts proliferative to secretory endometrium in the presence of adequate endogenous oestrogen.
• GnRH suppression: Reduces hypothalamic GnRH pulsatility → ↓ FSH & LH → follicular suppression (dose- and route-dependent).
• Cervical mucus thickening: Contributes to contraceptive efficacy of injectable formulations.
• Androgenic effects: Mild acnegenic and androgenic activity at the skin level; modest impact on lipid profile (↑ LDL, ↓ HDL with long-term use).
• Glucocorticoid receptor activity (high doses): Adrenal suppression, Cushingoid features, glucose intolerance possible with oncology-level dosing.
• Bone mineral density (parenteral, long-term): Suppression of ovarian oestrogen production leads to progressive BMD reduction with continued Depo-MPA use — particularly significant in adolescents during peak bone accrual.
• CNS: Mood changes, depression, insomnia — mechanism incompletely understood; likely mediated via hypothalamic serotonergic and GABAergic modulation.

Oral tablets begin working immediately but patients should be counselled that symptom improvement — particularly for heavy periods or endometriosis pain — may take one to three months to become fully apparent.

The principal clinical concern is not acute toxicity but rather long-term safety signals: BMD reduction with prolonged parenteral use, and cardiovascular/oncological risks when combined with oestrogen in HRT — neither of which constitutes narrow therapeutic index behaviour in the classical sense.

Laboratory Test Interference

MPA may alter the following laboratory parameters — results should be interpreted with caution in patients on therapy:

Injectable-Specific — Menstrual Changes Over Time

Menstrual irregularity is the single most common adverse effect of injectable MPA used as contraception:

• ~57% of users experience irregular bleeding or spotting at 12 months
• ~60–70% develop amenorrhoea by 12–24 months of use
• Weight gain > 10 lb in ~38% at 24 months

CYP3A4 Inducers — Reduce MPA Efficacy

MPA has a wide therapeutic index and acute overdose toxicity is low. No specific toxic serum concentration threshold is defined for standard oral doses.

Expected Signs of Overdose

• Nausea and vomiting
• Drowsiness and excessive fatigue
• Fluid retention and oedema
• Exaggeration of common adverse effects (breast tenderness, mood changes)

Oral LD₅₀: > 6,400 mg/kg (rat); > 16 g/kg (mouse). Confirms a very wide safety margin between therapeutic and lethal doses.

Pregnancy

MPA can affect the hormonal milieu of pregnancy. Injectable MPA is not recommended for women attempting to conceive, given the prolonged fertility delay post-discontinuation.

Lactation

Detectable but low amounts of MPA are excreted in breast milk. Infant absorption from breast milk is minimal.

• Standard oral doses: Generally considered compatible with breastfeeding by most international guidance. The American Academy of Pediatrics classifies progestins as compatible with breastfeeding.
• Injectable MPA: Should not be initiated until at least 6 weeks postpartum in breastfeeding women (to allow establishment of lactation), or 5 days postpartum in non-breastfeeding women.
• High-dose oncology MPA: Individual specialist assessment required — benefit-risk decision should involve the treating oncologist.

Clinicians should monitor infants for adequate feeding and normal development where maternal MPA therapy is ongoing.

Fertility

• Oral MPA: Fertility typically returns promptly after cessation.
• Injectable MPA: Median return of fertility is approximately 10 months post last injection, but can extend to 12–18 months. Patients planning pregnancy should be counselled about this delay before initiating injectable therapy.
• Ectopic pregnancy has been reported in cases of contraceptive failure with injectable MPA.

• Pre-pubertal children: Not indicated. MPA tablets are not licensed for paediatric use in children who have not yet reached menarche.
• Post-pubertal adolescent females: May be used for the same gynaecological indications as adults (secondary amenorrhoea, abnormal uterine bleeding, endometriosis) at standard adult doses. Specific paediatric dose-finding studies have not been conducted.
• BMD concern in adolescents: This is a particularly important consideration. Adolescence is a critical period of peak bone accrual. Long-term use of injectable depot MPA in adolescents may significantly impair peak bone mass, increasing long-term osteoporotic fracture risk. Injectable MPA should not be the first-line contraceptive choice in adolescents; if used, duration should be minimised and calcium/vitamin D supplementation and regular BMD monitoring should be considered.

• In the WHI estrogen plus progestin substudy, 44% of participants were ≥65 years, and 6.6% were ≥75 years.
• The elevated risks of probable dementia and cardiovascular events identified in the WHI were most pronounced in women ≥65 years receiving combined CE/MPA therapy.
• MPA in combination with oestrogen should not be used to prevent cognitive decline, dementia, or cardiovascular disease in older women.
• For women ≥65 using MPA as part of HRT for genuine symptom management, the lowest effective dose for the shortest necessary duration is the recommended approach.
• No specific dose adjustment guidelines for MPA monotherapy in the elderly based solely on age; however, age-related changes in hepatic metabolism and the higher prevalence of co-morbidities and polypharmacy in this population warrant careful monitoring.

• Generic availability: MPA is widely available as a generic in most markets. Generic tablets (2.5 mg, 5 mg, 10 mg) are significantly less expensive than branded equivalents.
• UK (NHS): Available on NHS prescription. Tablets dispensed under generic name or branded equivalents. Injectable Depo-Provera available at sexual and reproductive health clinics and GP surgeries. No patient prescription charge for those with exemption certificates.
• India: Available in multiple generic tablet brands across all tiers of healthcare. Widely accessible and inexpensive.
• US: Provera (branded) and generic MPA tablets widely available. Depo-Provera injection available at clinics. Covered under most insurance plans for contraception at no cost under ACA-mandated preventive services.
• High-dose formulations (100–400 mg): Less widely available; typically dispensed through specialist oncology pharmacy channels.

MPA is not a controlled substance in any major jurisdiction. It is universally classified as a prescription-only medicine and is not available over the counter.