Sex hormone combinations

Overview and Therapeutic Classification
Sex hormone combinations are pharmacological preparations containing two or more sex hormones, typically estrogens with progestins, or androgens with estrogens/progestins, designed to achieve specific hormonal balance or suppress endogenous hormone secretion. These combinations are used widely for contraception, menopausal hormone replacement therapy (HRT), management of hypogonadism, gender-affirming therapy, and treatment of various gynecological and endocrine conditions.

These formulations may be monophasic (fixed dose throughout the cycle), biphasic, triphasic, or extended-cycle in nature, depending on the dosing scheme and clinical objective.

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Types of Sex Hormone Combinations

1. Estrogen + Progestin Combinations

These are the most common combinations and are used in:

• Oral contraceptives (COCs)

• Hormone replacement therapy (HRT)

• Menstrual disorders

• Endometriosis

• Postmenopausal osteoporosis prevention

Common Estrogens Used:

• Ethinylestradiol (synthetic, most common in COCs)

• Estradiol (natural)

• Conjugated estrogens

• Estetrol (new-generation estrogen)

Common Progestins Used:

• Norethisterone (norethindrone)

• Levonorgestrel

• Drospirenone

• Desogestrel

• Norgestimate

• Medroxyprogesterone acetate (MPA)

• Dydrogesterone

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2. Estrogen + Androgen Combinations

Used for:

• Severe menopausal symptoms (off-label in some countries)

• Hypoactive sexual desire disorder (HSDD)

• Certain cases of hormone replacement in hypogonadal women

Examples:

• Estradiol + Methyltestosterone (e.g., Estratest)

• Not widely used due to virilization risks and limited regulatory approval

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3. Progestin + Androgen Combinations

Rare in current clinical use but previously explored for:

• Hormonal contraceptives

• Treatment of endometriosis or fibroids

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Common Indications

Clinical Use	Hormonal Components
Combined Oral Contraceptives (COCs)	Estrogen + Progestin
Hormone Replacement Therapy (HRT)	Estrogen + Progestin or Androgen
Gender-Affirming Therapy	Estrogen + Antiandrogen, Progestin (MTF); Testosterone + Progestin (FTM)
Dysfunctional Uterine Bleeding	Estrogen + Progestin
Endometriosis	Estrogen + Progestin (cyclical or continuous)
Polycystic Ovary Syndrome (PCOS)	Estrogen + Progestin
Hypogonadism	Estrogen + Progestin or Androgen

Examples of Formulations and Brand Names

Brand Name	Components	Use
Yasmin	Ethinylestradiol + Drospirenone	Contraceptive
Microgynon	Ethinylestradiol + Levonorgestrel	Contraceptive
Femoston	Estradiol + Dydrogesterone	HRT
Premique	Conjugated Estrogens + MPA	HRT
Qlaira	Estradiol valerate + Dienogest	Contraceptive / HRT
Estratest (US)	Esterified Estrogens + Methyltestosterone	Menopause (off-label in many countries)
Activelle	Estradiol + Norethisterone	HRT
Angelique	Estradiol + Drospirenone	HRT
NuvaRing	Ethinylestradiol + Etonogestrel (vaginal)	Contraceptive

Formulations and Routes

• Oral tablets – most common for contraceptives and HRT

• Transdermal patches – consistent hormone levels, better for women with liver issues

• Vaginal rings – localized and systemic effects (e.g., NuvaRing)

• Injectables – less common for combination use (most injectables are progestin-only)

• Implants – generally progestin-only, but some combinations under research

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Mechanism of Action

Estrogen + Progestin combinations:

• Suppress ovulation by inhibiting gonadotropin (LH and FSH) release via negative feedback

• Thicken cervical mucus to prevent sperm penetration

• Alter endometrial lining to prevent implantation

• In HRT, restore hormonal balance and alleviate menopausal symptoms

Estrogen + Androgen combinations:

• Improve libido, sexual function, and energy levels (off-label use)

• Androgenic effect may support anabolic and mood-stabilizing benefits

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Adverse Effects

Component	Common Side Effects	Serious Risks
Estrogens	Breast tenderness, nausea, bloating	Venous thromboembolism (VTE), stroke, cancer
Progestins	Mood swings, bloating, acne (depending on agent)	Depression, breast cancer, insulin resistance
Androgens	Hirsutism, acne, voice deepening	Liver toxicity, cardiovascular risks

Contraindications

Condition	Reason
Thromboembolic disorders	↑ clot risk with estrogens
Breast or estrogen-dependent cancer	Stimulated by hormonal therapy
Liver dysfunction	Steroids undergo hepatic metabolism
Pregnancy	Not indicated except for hormone support cases
Unexplained vaginal bleeding	Require evaluation prior to initiating hormones

Drug Interactions

Interacting Drug	Effect on Sex Hormone Combinations
CYP3A4 inducers (e.g., rifampin, phenytoin)	↓ estrogen/progestin levels → contraceptive failure
Antibiotics (e.g., rifampin)	Interfere with enterohepatic recirculation
Warfarin	Estrogens may antagonize anticoagulant effect
Corticosteroids	Androgens may potentiate catabolic or fluid retention effects
Antidiabetic drugs	Estrogens may worsen insulin resistance

Clinical Considerations and Monitoring

Population/Condition	Clinical Consideration
Adolescents	COC for menstrual regulation or contraception
Postmenopausal women	HRT benefits vs risks (e.g., breast cancer)
Smokers over 35	Avoid COCs due to VTE risk
Obesity	Monitor for cardiovascular risks with estrogen use
Transgender patients	Tailored regimens, often include antiandrogens

Monitoring Requirements

Parameter	Frequency/Indication
Blood pressure	Regularly, especially with estrogen use
Liver function tests	Baseline and periodically
Lipids and glucose	In long-term users or metabolic risk patients
Mammography	Annually in HRT users
Endometrial monitoring	With unopposed estrogen or abnormal bleeding

Clinical Guidelines and Recommendations

• Combined Oral Contraceptives (COCs):

  • Use lowest effective estrogen dose (e.g., 20–30 mcg EE)

  • Avoid estrogen in high-VTE risk groups (use progestin-only instead)

• HRT:

  • Use for shortest duration necessary

  • In women with uterus, always combine estrogen with progestin to reduce endometrial cancer risk

• Gender-Affirming Therapy:

  • Requires specialist-guided hormone titration

  • Estrogen + antiandrogen regimens may be used in transgender women

  • Testosterone + progestin used in transgender men (if contraception or endometrial suppression required)

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Comparative Summary Table

Combination Type	Key Benefit	Key Limitation
Estrogen + Progestin	Contraception, menstrual control	VTE risk, mood changes
Estrogen + Androgen	Libido, energy, menopause (off-label)	Virilization, lipid changes
Phasic Combinations	Mimic natural cycle	More complex compliance
Continuous Combinations	No withdrawal bleeding	May cause spotting, adherence required