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Monday, August 4, 2025

Progestins


Progestins are synthetic compounds designed to mimic the effects of the naturally occurring hormone progesterone. They play a central role in various physiological processes related to the female reproductive system, particularly the menstrual cycle and pregnancy. Progestins are widely used in several therapeutic areas, including contraception, hormone replacement therapy (HRT), treatment of endometriosis, abnormal uterine bleeding, and certain cancers such as endometrial and breast cancer.


1. Classification of Progestins

Progestins are broadly classified based on their structural similarity to either:

  • Progesterone (pregnane derivatives)

  • Testosterone (estrane and gonane derivatives)

A. Pregnane Derivatives (Natural-like Progestins)

  • Structurally related to natural progesterone

  • Examples: medroxyprogesterone acetate (MPA), megestrol acetate, dydrogesterone

B. Estrane Derivatives (19-nortestosterone derivatives)

  • Derived from testosterone and possess weak androgenic activity

  • Examples: norethindrone, norethindrone acetate, lynestrenol

C. Gonane Derivatives (Subgroup of 19-nortestosterone)

  • Modified to reduce androgenic activity and increase progestational potency

  • Examples: levonorgestrel, desogestrel, gestodene, norgestimate

D. Spironolactone-derived Progestins

  • Have antiandrogenic and antimineralocorticoid effects

  • Example: drospirenone

2. Mechanism of Action

Progestins exert their effects primarily by binding to progesterone receptors (PR), which are nuclear hormone receptors. Once bound, the progestin-receptor complex modulates gene transcription to produce physiological effects.

Key actions include:

  • Suppressing the luteinizing hormone (LH) surge, thereby inhibiting ovulation

  • Enhancing the transformation of the endometrium to a secretory state, supporting potential embryo implantation

  • Increasing cervical mucus viscosity, hindering sperm penetration

  • Reducing uterine contractility, stabilizing the endometrium

  • Causing endometrial atrophy with prolonged use, which is beneficial in endometrial hyperplasia or cancer

3. Therapeutic Uses

A. Contraception

  • Progestins are used in various contraceptive formulations:

    • Combined oral contraceptives (with estrogen)

    • Progestin-only pills (mini-pill)

    • Long-acting injectables (e.g., depot medroxyprogesterone acetate)

    • Implants (e.g., etonogestrel)

    • Intrauterine devices (e.g., levonorgestrel IUD)

B. Hormone Replacement Therapy (HRT)

  • Used with estrogens in postmenopausal women to prevent estrogen-induced endometrial hyperplasia

C. Endometriosis

  • Suppress the growth of ectopic endometrial tissue and reduce associated pain

D. Abnormal Uterine Bleeding

  • Stabilize the endometrium and regulate menstrual cycles

E. Endometrial and Breast Cancers

  • Megestrol acetate and medroxyprogesterone are used in palliative treatment to counteract estrogen-driven proliferation

F. Menstrual Disorders

  • Induce withdrawal bleeding in amenorrhea or correct luteal phase deficiency

G. Cachexia in Cancer and AIDS

  • Megestrol acetate is used for appetite stimulation and weight gain

4. Pharmacokinetics

Absorption: Most oral progestins are rapidly absorbed. Bioavailability varies between agents.

Distribution: Extensively bound to plasma proteins (albumin, corticosteroid-binding globulin). Lipophilic, so they accumulate in adipose tissue.

Metabolism:

  • Primarily in the liver via reduction, hydroxylation, and conjugation

  • Some progestins (e.g., desogestrel) are prodrugs and require hepatic activation

Elimination:

  • Excreted via urine and feces

  • Half-life varies widely depending on the compound and route (e.g., depot forms have half-lives of several weeks)

5. Types of Progestins and Generic Drug Names

A. First-generation (Estranes)

  • Norethindrone

  • Norethindrone acetate

  • Lynestrenol

B. Second-generation (Gonanes)

  • Levonorgestrel

  • Norgestrel

C. Third-generation (Modified Gonanes)

  • Desogestrel

  • Gestodene

  • Norgestimate

D. Fourth-generation

  • Drospirenone

  • Dienogest

  • Nomegestrol acetate

E. Pregnane derivatives

  • Medroxyprogesterone acetate (MPA)

  • Megestrol acetate

  • Dydrogesterone

  • Hydroxyprogesterone caproate

6. Side Effects

Common adverse effects:

  • Menstrual irregularities (spotting, amenorrhea)

  • Nausea

  • Breast tenderness

  • Headache

  • Weight changes

  • Acne and oily skin (especially with androgenic progestins)

  • Mood changes and depression

  • Bloating

Serious adverse effects:

  • Increased risk of thromboembolism (especially in combination with estrogen)

  • Decreased HDL cholesterol (with androgenic progestins)

  • Osteopenia/osteoporosis with long-term use of depot MPA

  • Possible increased risk of breast cancer with long-term use (under investigation)

7. Contraindications

  • Known or suspected pregnancy (unless used to support pregnancy)

  • Active or history of breast cancer or hormone-dependent malignancies

  • Unexplained vaginal bleeding

  • Active thromboembolic disorders

  • Severe hepatic impairment

  • Hypersensitivity to any component of the formulation

8. Precautions

  • Monitor patients with depression, as progestins may exacerbate mood disorders

  • Use caution in individuals with diabetes, hypertension, asthma, migraine, or seizure disorders

  • Consider bone mineral density monitoring for prolonged use of depot medroxyprogesterone

  • Use of drospirenone requires monitoring of potassium levels, especially in patients on ACE inhibitors, ARBs, or potassium-sparing diuretics

9. Drug Interactions

Enzyme inducers (e.g., rifampicin, phenytoin, carbamazepine, St. John’s Wort):

  • May reduce plasma levels of progestins and decrease effectiveness

Antiretroviral drugs:

  • Protease inhibitors and NNRTIs may alter progestin metabolism

Antibiotics:

  • Gut flora alteration by broad-spectrum antibiotics may reduce enterohepatic circulation of estrogen-progestin contraceptives, but evidence is inconclusive

Drospirenone interactions:

  • As it has antimineralocorticoid activity, it can increase serum potassium when used with potassium-sparing drugs

Warfarin:

  • Potential alteration of anticoagulant effect; monitor INR

10. Comparison of Selected Progestins

Medroxyprogesterone acetate (MPA):

  • Strong progestogenic activity

  • Used in HRT, contraception (depot form), and cancer

  • Androgenic activity: moderate

Levonorgestrel:

  • High progestational potency

  • Used in oral pills, IUDs, emergency contraception

  • Androgenic activity: high

Desogestrel:

  • Prodrug with low androgenicity

  • Used in third-generation contraceptive pills

Drospirenone:

  • Antiandrogenic and antimineralocorticoid properties

  • Used in contraceptives for acne-prone women or those with fluid retention

Dienogest:

  • Antiandrogenic profile

  • Used in endometriosis treatment and HRT

11. Special Considerations in Contraceptive Use

Emergency Contraception:

  • Levonorgestrel (single dose 1.5 mg or 0.75 mg x 2 doses)

  • Most effective if taken within 72 hours after intercourse

Long-acting Reversible Contraception (LARC):

  • Depot MPA: every 3 months IM or SC

  • Levonorgestrel-releasing IUD: effective for up to 5 years

  • Etonogestrel implants: effective for 3 years

Perimenopausal HRT:

  • Use combined estrogen-progestin regimens cyclically or continuously

  • Progestin is essential to protect against endometrial hyperplasia

12. Role in Oncology

Endometrial carcinoma:

  • High-dose MPA or megestrol acetate is used in advanced or recurrent disease

Breast cancer (palliative):

  • Megestrol acetate is occasionally used for appetite stimulation or hormone suppression

Progestins in transgender care:

  • Used as part of feminizing hormone therapy in transfeminine individuals to suppress testosterone

13. Use in Pregnancy

While some natural progesterone formulations (e.g., micronized progesterone) are used in early pregnancy support, especially in cases of luteal phase defect or in assisted reproductive technologies, most synthetic progestins are not recommended during pregnancy unless specifically indicated.

14. Novel and Emerging Progestins

Nestorone:

  • A newer progestin under research for transdermal contraceptive delivery

  • High selectivity for progesterone receptors

  • Minimal androgenic, estrogenic, or glucocorticoid activity

Nomegestrol acetate:

  • Used in combination with estradiol for HRT and contraception

  • Highly selective for progesterone receptors with negligible androgenic activity

15. Summary of Generic Progestin Drugs

  • Medroxyprogesterone acetate

  • Megestrol acetate

  • Norethindrone

  • Norethindrone acetate

  • Levonorgestrel

  • Desogestrel

  • Etonogestrel

  • Drospirenone

  • Dienogest

  • Dydrogesterone

  • Hydroxyprogesterone caproate

  • Norgestimate

  • Gestodene

  • Nomegestrol acetate

  • Norgestrel

  • Lynestrenol



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