What are the indications, dosing regimen, contraindications, adverse effects, monitoring requirements, and alternative therapies for Aygestin (medroxyprogesterone acetate)?

Aygestin (Norethisterone Acetate): Clinical Overview

Indications

Aygestin is indicated for endometriosis, abnormal uterine bleeding due to hormonal imbalance, secondary amenorrhea, and as a component of hormone replacement therapy in postmenopausal women with an intact uterus. 1

Primary Indications:

• Fertility-sparing therapy for grade 1, stage IA endometrial adenocarcinoma in highly selected patients who wish to preserve fertility, though medroxyprogesterone acetate or megestrol acetate are more commonly recommended 1
• Endometrial hyperplasia without atypia as part of progestin-based treatment regimens 2, 3, 4
• Abnormal uterine bleeding in adolescents and reproductive-age women when administered cyclically 5
• Hormone replacement therapy as endometrial protection when combined with estrogen in postmenopausal women with intact uterus 1, 6

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Dosing Regimens

For Endometrial Hyperplasia:

• 15 mg daily for 10 days per menstrual cycle for simple endometrial hyperplasia without atypia, with re-evaluation by endometrial sampling every 3 months 3, 4
• Continue for 3-6 months with repeat endometrial biopsy to assess regression 2, 3, 4

For Abnormal Uterine Bleeding:

• Adolescents and reproductive-age women: 5-15 mg daily for 10 days each month for ≥3 months, with close monitoring thereafter 5
• Perimenopausal women: Cyclic administration for days 18-25 of a 25-day cycle when combined with conjugated equine estrogens 5

For Hormone Replacement Therapy:

• 1 mg daily continuously when combined with transdermal estradiol 50-100 mcg/day for continuous combined regimens 6
• 5 mg daily for 12-14 days per month when used in sequential regimens with estrogen 6

For Endometriosis:

• Higher doses (not specifically norethisterone acetate, but related progestins like medroxyprogesterone acetate at 50 mg daily) have been used for 4 months with good efficacy 7

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Contraindications

Absolute Contraindications:

• Active or history of breast cancer or other hormone-sensitive malignancies 1
• Current or history of venous thromboembolism (deep vein thrombosis, pulmonary embolism) 1
• Active arterial thromboembolic disease (stroke, myocardial infarction) 1
• Active liver disease or hepatic dysfunction 6
• Undiagnosed abnormal uterine bleeding requiring evaluation before treatment 1
• Known or suspected pregnancy 1

Relative Contraindications:

• Smoking, particularly in women over 35 years, significantly increases cardiovascular risk 1
• Hereditary angioedema (HAE-C1-INH): Norethisterone derivatives can be used but require careful monitoring, as some patients tolerate them well while others may experience worsening symptoms 1

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Adverse Effects

Common Side Effects:

• Breakthrough bleeding occurs in approximately 20% of patients on continuous progestin therapy 7
• Amenorrhea develops in up to 75% of patients on higher-dose continuous regimens 7
• Weight gain and fluid retention are common complaints 1
• Mood changes including depression and irritability 1

Metabolic and Cardiovascular Effects:

• Adverse effects on lipid profiles with potential increases in LDL cholesterol 1
• Negative impact on vasomotion and carbohydrate metabolism compared to micronized progesterone 1
• Increased blood pressure and activation of the renin-angiotensin system, particularly when combined with ethinyl estradiol 1

Serious Adverse Effects:

• Increased cardiovascular risk when used long-term in hormone replacement therapy, though less than with medroxyprogesterone acetate 1, 6
• Potential thrombotic risk, though lower than combined oral contraceptives containing ethinyl estradiol 1

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Monitoring Requirements

Initial and Ongoing Monitoring:

• Endometrial sampling (biopsy or D&C) every 3-6 months when used for fertility-sparing therapy in endometrial cancer or endometrial hyperplasia 1, 2, 3
• Clinical evaluation monthly during initial treatment for abnormal uterine bleeding to assess bleeding patterns 5
• Annual clinical review focusing on compliance, bleeding patterns, symptom control, and reassessment of risks versus benefits when used in hormone replacement therapy 6, 8
• Blood pressure monitoring at each visit, particularly in women with hypertension or cardiovascular risk factors 1

Specific Monitoring for Fertility-Sparing Therapy:

• Total hysterectomy with bilateral salpingo-oophorectomy (TH/BSO) with staging is recommended if endometrial cancer persists after 6-12 months of progestin therapy, if progression occurs on biopsy, or after childbearing is complete 1
• Imaging studies (pelvic MRI) should be performed after 6 months of failed hormonal therapy to exclude myoinvasion and nodal/ovarian metastasis before continuing fertility-sparing therapy 1

Laboratory Monitoring:

• No routine laboratory monitoring is required unless specific symptoms or concerns arise (e.g., liver function tests if hepatic symptoms develop) 6, 8

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Alternative Therapies

Preferred Alternatives for Hormone Replacement Therapy:

• Micronized progesterone 200 mg daily for 12-14 days per month is the first-line progestin choice due to superior cardiovascular and thrombotic safety profile compared to synthetic progestins like norethisterone acetate 1, 6
• Dydrogesterone 10 mg daily for 12-14 days per month or 5 mg daily continuously is recommended by ESHRE as an alternative with favorable safety profile 1, 6

Alternatives for Endometrial Hyperplasia:

• Medroxyprogesterone acetate 10 mg daily for 10-14 days per cycle shows similar efficacy to norethisterone acetate (36.7% vs 37% resolution rates) 3, 4
• Levonorgestrel-releasing intrauterine system (LNG-IUS) demonstrates superior efficacy with 66.67% resolution rate at 3 months compared to 40% with oral norethisterone 3
• Lynestrenol 15 mg daily for 10 days per cycle shows highest resolution rate (56%) among oral progestins, though not statistically significant 4

Alternatives for Fertility-Sparing Therapy in Endometrial Cancer:

• Medroxyprogesterone acetate or megestrol acetate are more commonly recommended than norethisterone acetate, with complete response rates of approximately 50% 1
• Levonorgestrel-releasing intrauterine device is an alternative option for local progestin delivery 1

Non-Hormonal Alternatives for Abnormal Uterine Bleeding:

• Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce menstrual blood loss in ovulatory dysfunctional uterine bleeding 5
• Antifibrinolytic agents (tranexamic acid) are effective for reducing menstrual blood loss 5
• Endometrial ablation or hysterectomy for patients who fail medical management and no longer desire fertility 5

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Critical Clinical Pitfalls

Common Errors to Avoid:

• Never use norethisterone acetate alone without estrogen in perimenopausal women requiring hormone therapy, as unopposed progestin may increase endometrial cancer risk 6
• Do not use norethisterone acetate for fewer than 10-12 days per cycle in sequential regimens, as shorter durations provide inadequate endometrial protection 1, 6
• Avoid combining norethisterone acetate with tranexamic acid due to potentially greater risk of venous thrombosis 1
• Do not use cyproterone acetate (another progestin) in women with hereditary angioedema, as it can worsen HAE-C1-INH symptoms 1
• Recognize that norethisterone acetate has less favorable cardiovascular and metabolic profiles than micronized progesterone, making it a second-line choice for hormone replacement therapy 1, 6

Special Population Considerations:

• In young women with chemotherapy or radiation-induced premature ovarian insufficiency, avoid anti-androgenic progestins and consider micronized progesterone as first-line due to better metabolic and cardiovascular profiles 1
• In women with hereditary angioedema, norethisterone derivatives have been used with variable tolerance; lynestrenol has shown good results in some patients, but careful monitoring is essential 1