What are the side effects of Hormone Replacement Therapy (HRT) progesterone (progestin)?

From the Guidelines

Progesterone in hormone replacement therapy (HRT) can cause several side effects, and the most recent evidence suggests that micronized progesterone (like Prometrium) at 100-200mg daily is often better tolerated than synthetic progestins like medroxyprogesterone acetate. Common side effects include breast tenderness, bloating, mood changes, headaches, and fatigue. Some women experience digestive issues like nausea or constipation. Progesterone may also cause dizziness, vaginal discharge, or breakthrough bleeding, especially during the first few months of treatment. More serious but less common side effects include blood clots, stroke risk, and potential increased risk of breast cancer with long-term use.

Key Points to Consider

• The delivery method affects side effects - oral progesterone often causes more drowsiness and may be taken at bedtime, while topical forms typically have fewer systemic effects.
• Micronized progesterone has a more favorable profile in terms of minimizing hormonal-related cardiovascular risks and has a neutral or beneficial effect on blood pressure compared to synthetic progestogens 1.
• The safety profile of micronized progesterone shows one of the best safety profiles in terms of thrombotic risk, although further supporting evidence regarding its effectiveness in the POI population is needed 1.
• Side effects typically diminish after the first few months as your body adjusts to the hormone.
• If side effects are severe or persistent, your healthcare provider may adjust your dosage or recommend a different form of progesterone to find the best balance between symptom relief and minimal side effects.

Recommendations

• Clinicians should choose between a sequential and continuous regimen of administration, with the latter preventing withdrawal bleeding.
• The dose of progestogen is based on the concurrent dose of estrogen administered.
• One of the advantages of the cyclic administration is that it would allow an earlier recognition of a pregnancy: as women with POI may spontaneously, though infrequently, ovinate, in the absence of a withdrawal bleeding 1.

From the FDA Drug Label

Serious, but less common side effects include: Risk to the Fetus: Cases of cleft palate, cleft lip, hypospadias, ventricular septal defect, patent ductus arteriosus, and other congenital heart defects. Abnormal Blood Clotting: Stroke, heart attack, pulmonary embolus, visual loss or blindness Some of the warning signs of serious side effects include: Changes in vision or speech Sudden new severe headaches Severe pains in your chest or legs with or without shortness of breath, weakness and fatigue Dizziness and faintness Vomiting Less serious, but common side effects include: Headaches Breast pain Irregular vaginal bleeding or spotting Stomach or abdominal cramps, bloating Nausea and vomiting Hair loss Fluid retention Vaginal yeast infection

The side effects of Hormone Replacement Therapy (HRT) progesterone (progestin) include:

• Serious side effects: + Risk to the fetus + Abnormal blood clotting (e.g. stroke, heart attack, pulmonary embolus)
• Common side effects: + Headaches + Breast pain + Irregular vaginal bleeding or spotting + Stomach or abdominal cramps, bloating + Nausea and vomiting + Hair loss + Fluid retention + Vaginal yeast infection 2

From the Research

Side Effects of Hormone Replacement Therapy (HRT) Progesterone (Progestin)

• The side effects of progestogen intake include bleeding problems, symptoms of fluid retention, adverse effects on skin, lipids, vasculature, and insulin resistance, as well as negative mood effects 3.
• Progestogen intolerance is a main factor for reduced compliance with hormone replacement therapy (HRT), and can be managed by manipulating the dosage and duration of progestogen, using continuous administration of a low dose of progestogen, and reducing the number of progestogenic episodes 3.
• The use of progestogen and progesterone releasing coils and vaginal progesterone gel can minimize systemic side effects and bleeding 3.
• Adverse effects of progestogen can also be avoided by using progesterone receptor-specific progestogens such as the pregnanes (e.g. cyproterone), nor-pregnanes (e.g. nomegestrol), and progesterone itself 3.
• Side effects of progestin-only therapy for menopausal symptoms include headaches and vaginal bleeding, which can lead to discontinuation of treatment in 6% to 21% of patients 4.
• Combined estrogen/progestogen therapy increases the risk of breast cancer when used for more than three to five years, and can also cause irregular bleeding and spotting 5, 6.
• The risk of endometrial hyperplasia and endometrial cancer can be reduced by using progestogen in combination with estrogen therapy, and by using continuous combined HRT regimens rather than sequential regimens 7, 6.