Sex hormones and hormonal contraceptives

Quick revision

Combined hormonal contraceptives, progestin-only methods, menopausal hormone therapy and testosterone replacement all deliver a sex steroid, but the safety conversation for each is different: VTE and age-plus-smoking for combined methods, bone density for depot medroxyprogesterone, endometrial cancer for unopposed estrogen, and virilization-by-secondary-exposure for topical testosterone.

• Combined hormonal contraceptives (estrogen plus progestin) raise venous thromboembolism risk to roughly 3 to 9 cases per 10,000 woman-years, a rate that is still compared against the background risk of VTE in pregnancy when patients weigh the decision. (1)
• Women over 35 who smoke should not use combined hormonal contraceptives; the boxed warning on these products exists specifically because cigarette smoking sharply increases serious cardiovascular events in that age-and-exposure combination. (1)
• Migraine with aura, a personal history of VTE or arterial thromboembolic disease, uncontrolled hypertension and current or past breast cancer are all listed contraindications to combined hormonal contraceptives. (1)
• Progestin-only methods — the levonorgestrel intrauterine system, the etonogestrel implant, and depot medroxyprogesterone acetate injection — avoid the estrogen-driven VTE signal but each carries its own labelled trade-off: irregular bleeding, an insertion/removal procedure, or reversible bone mineral density loss. (3) (4) (2)
• Depot medroxyprogesterone acetate's own boxed warning covers bone mineral density loss that is greater with longer use and may not fully reverse, which is why the label advises against using it as a birth control method for longer than two years unless other options are inadequate. (2)
• Unopposed estrogen therapy in a woman with an intact uterus raises endometrial cancer risk roughly two to twelve-fold; adding a progestin is the labelled way to reduce that risk, which is the whole rationale for combined rather than estrogen-alone menopausal hormone therapy in these patients. (5)
• The Women's Health Initiative findings behind the menopausal hormone therapy boxed warning include increased stroke, deep vein thrombosis, pulmonary embolism and myocardial infarction with estrogen-plus-progestin, increased invasive breast cancer with longer combined use, and increased probable dementia in women 65 and older. (6)
• Topical testosterone's boxed warning is about virilization from secondary exposure — children or partners who contact an unwashed application site can develop signs of androgen exposure themselves, which is a transfer risk rather than a risk to the treated patient. (7)

Overview

This class covers four uses of the same small family of steroid hormones — estrogens, progestins and androgens — rather than one drug mechanism applied to one disease. Combined hormonal contraceptives and progestin-only contraceptives prevent pregnancy; menopausal hormone therapy replaces the estrogen (and, when the uterus is present, the progestin) that ovarian function stops supplying at menopause; testosterone replacement restores androgen levels in men with confirmed hypogonadism. What ties them together for exam and prescribing purposes is not a shared target but a shared question: how much estrogen, by which route, and is the uterus (or, for testosterone, a child in the household) part of the risk calculation. (8)

In combined hormonal contraception, progestin does most of the contraceptive work by suppressing ovulation, and the added estrogen chiefly stabilises the endometrium so that predictable withdrawal bleeding occurs; the estrogen component is also the one that drives the venous thromboembolism signal. That VTE risk is quoted in the labelling as roughly 3 to 9 cases per 10,000 woman-years of use, and it is why the same class carries a boxed warning restricting use in women over 35 who smoke — smoking sharply compounds the cardiovascular risk that estrogen alone already raises at that age. (8) (1)

Progestin-only methods were built around avoiding that estrogen-linked VTE signal while keeping contraceptive efficacy high. The levonorgestrel intrauterine system and the etonogestrel subdermal implant work largely locally or through ovulation suppression with minimal systemic estrogen exposure, and depot medroxyprogesterone acetate suppresses gonadotropin release systemically without an estrogen component at all. None of the three shares the combined-method VTE boxed warning, but each has its own labelled cost: unpredictable bleeding patterns for the first two, and a bone-mineral-density warning specific to the depot injection. (3) (4) (2)

Menopausal hormone therapy turns the same estrogen-and-uterus question around. Estrogen alone relieves menopausal symptoms effectively, but in a woman who still has a uterus it also stimulates endometrial proliferation unopposed, and the labelling for conjugated estrogens states the resulting endometrial cancer risk runs roughly two to twelve times that of non-users, tracking with dose and duration. Adding a progestin restores the endometrial protection that a woman's own ovaries would otherwise provide across a natural cycle, which is the entire pharmacological reason estrogen-plus-progestin products such as conjugated estrogens with medroxyprogesterone acetate exist as a distinct combination rather than estrogen simply being dosed alone in every patient. A woman without a uterus, by contrast, has no endometrium to protect and is typically offered estrogen alone. (5) (6)

Testosterone replacement sits apart from the other three uses mechanistically — it restores androgen signalling in confirmed male hypogonadism rather than manipulating a female reproductive cycle — but it belongs in the same class because it is the same steroid-hormone-replacement logic applied to a different axis, and it carries its own transfer-risk boxed warning: unwashed skin after topical application can virilise a child or partner who makes secondary contact with it. (7)

Classification and drug examples

Four groups share this class not because they act on one receptor the same way, but because each is a clinical use of estrogen, progestin or androgen replacement with its own dominant safety question.

Mechanism of action

All four groups act through the same basic pharmacology — a steroid hormone (or a synthetic analogue) binding its intracellular nuclear receptor and altering gene transcription — applied to different physiological targets. In contraception, exogenous progestin (with or without estrogen) suppresses the hypothalamic-pituitary-gonadal axis strongly enough to blunt the LH surge and prevent ovulation, while also thickening cervical mucus and altering the endometrium as backup mechanisms. In menopausal hormone therapy, exogenous estrogen replaces what the postmenopausal ovary no longer supplies, relieving vasomotor and genitourinary symptoms, while an added progestin opposes estrogen's proliferative effect on the endometrium in a woman who still has a uterus. In androgen replacement, exogenous testosterone restores androgen-receptor signalling that is deficient because of primary gonadal failure or hypothalamic-pituitary failure.

Molecular target

Nuclear estrogen, progesterone and androgen receptors, plus estrogen and progestin negative feedback on the hypothalamic-pituitary-gonadal axis

Pharmacodynamic effect

Not applicable — these are hormone receptor agonists modulating gene transcription and endocrine feedback loops rather than cytotoxic or cytostatic agents acting on a pathogen

Effect kinetics

Onset and offset are route- and use-dependent: cervical mucus thickening from a progestin can occur within days, ovulation suppression typically needs a full treatment cycle to be reliable, depot medroxyprogesterone's effect persists for months after the last injection because of its slow-release depot, and an implant or intrauterine system's effect reverses only once it is removed

1. Exogenous progestin (with or without estrogen) is absorbed by the labelled route

   Oral tablets, a subdermal implant, an intrauterine system, or a depot intramuscular or subcutaneous injection each deliver the hormone into the circulation or, for the intrauterine system, largely into the local uterine environment. (3) (8)

2. Progestin suppresses gonadotropin-releasing hormone pulsatility and blunts the LH surge

   Depot medroxyprogesterone's label describes this directly: the progestin primarily inhibits gonadotropin secretion, which prevents follicular maturation and ovulation. (2)

3. Cervical mucus thickens and the endometrium becomes less receptive

   The etonogestrel implant's label lists cervical mucus viscosity increase and endometrial alteration alongside ovulation suppression as its three contraceptive mechanisms, and the intrauterine system produces the mucus and endometrial effects locally with comparatively little reliance on ovulation suppression. (4) (3)

4. In menopausal hormone therapy, estrogen instead activates endometrial and other target-tissue estrogen receptors

   Without an opposing progestin, that estrogen receptor activation drives endometrial proliferation in a woman with an intact uterus, which is the mechanistic root of the unopposed-estrogen endometrial cancer signal. (5)

5. Adding a progestin (menopausal hormone therapy) or testosterone acting on the androgen receptor (male hypogonadism) completes the intended replacement

   A co-administered progestin counteracts the proliferative estrogen effect on the endometrium, while exogenous testosterone binds the androgen receptor directly to restore signalling that primary or secondary hypogonadism has removed. (6) (7)

Major clinical uses

Pharmacokinetics

• This page gives no dose regimens by design. Specific dosing for any contraceptive method, hormone therapy regimen or testosterone product depends on the individual patient, the product formulation and a current prescribing reference.
• Route drives risk as much as the hormone itself does in this class: an intrauterine or implanted progestin acts largely locally with limited systemic exposure, while an oral estrogen passes through the liver on every dose in a way that a transdermal patch does not, which is part of why route is discussed alongside dose in shared decision-making for both contraception and menopausal therapy. (5) (3)

Adverse effects

Common

• Irregular or unpredictable bleeding: Reported across progestin-only methods including the intrauterine system and the implant, and is one of the most common reasons patients discontinue these methods. (3) (4)
• Headache: A commonly reported effect across combined and progestin-only hormonal contraceptives, and also reported with testosterone replacement and menopausal hormone therapy. (3) (4)
• Weight change, acne and breast tenderness: Reported with the etonogestrel implant among its most common adverse reactions (each affecting at least one in ten users in trials). (4)
• Mood changes: The etonogestrel implant's label specifically advises careful observation of women with a history of depressed mood, with removal considered if significant depression develops. (4)

Serious adverse effects

• Venous thromboembolism: The defining risk of the estrogen-containing combined methods, estimated at 3 to 9 cases per 10,000 woman-years; not shared to the same degree by progestin-only methods, which lack the estrogen component driving the effect. New leg swelling, chest pain or breathlessness during use of any estrogen-containing product is an urgent reason to seek care rather than wait. (1)
• Cardiovascular events with combined hormonal contraceptives in smokers over 35: The boxed warning specifically restricts use in women over 35 who smoke, because cigarette smoking substantially increases serious cardiovascular events in combined hormonal contraceptive users in this age group. Smoking cessation counselling and switching to a non-estrogen-containing method are the labelled responses rather than continuing combined use unmodified. (1)
• Bone mineral density loss with depot medroxyprogesterone acetate: Greater with longer duration of use and may not be completely reversible; adolescent use during a critical bone-accretion period raises uncertainty about later fracture risk that the label states has not been resolved. The label advises against using this method for longer than 2 years unless other contraceptive options are considered inadequate. (2)
• Endometrial cancer with unopposed estrogen: Roughly two to twelve times the risk of non-users in a woman with an intact uterus taking estrogen without a progestin, tracking with dose and duration of use. A progestin is added for endometrial protection in any woman with a uterus receiving estrogen therapy for menopausal symptoms. (5)
• Stroke, deep vein thrombosis, pulmonary embolism and myocardial infarction with estrogen-plus-progestin menopausal therapy: Identified in the Women's Health Initiative estrogen-plus-progestin substudy over roughly 5.6 years of treatment; the label states menopausal hormone therapy should not be used for cardiovascular disease prevention. Cardiovascular risk factors are assessed and weighed against symptom severity before starting or continuing menopausal hormone therapy. (6)
• Invasive breast cancer with estrogen-plus-progestin menopausal therapy: An increased risk was demonstrated in the same Women's Health Initiative substudy with longer-term combined use. Current or past breast cancer is a contraindication, and breast surveillance continues during treatment per routine care. (6)
• Probable dementia in women 65 and older on combined menopausal hormone therapy: The Women's Health Initiative Memory Study found an increased risk in this age group; applicability to younger women starting therapy closer to menopause has not been established in the same way. Age at initiation is one factor the treating clinician weighs in the individualised risk-benefit discussion. (6)
• Ectopic pregnancy with the levonorgestrel intrauterine system: The label states that roughly half of pregnancies that do occur with the device in place are ectopic, even though overall pregnancy rates with the method are very low. New pelvic pain or other symptoms suggestive of pregnancy with the device in place warrant prompt clinical evaluation. (3)
• Virilization from secondary testosterone exposure: Children and, less commonly, female partners who have unwashed skin-to-skin contact with a testosterone gel application site can develop signs of androgen exposure themselves, which is the subject of the product's boxed warning. Covering the application site, hand-washing after application and avoiding skin contact until the product has dried are labelled precautions, not optional advice. (7)

Drug-specific effects

• Depot medroxyprogesterone acetate: The only method in this class with a labelled duration cap (2 years) tied specifically to its own boxed warning rather than to general contraceptive counselling. (2)
• Levonorgestrel intrauterine system: Carries a distinct insertion-related risk profile (uterine perforation, expulsion, and a reported association with group A streptococcal infection following insertion) that an oral or injectable method does not share. (3)
• Testosterone gel: The only agent in this class whose principal boxed-warning risk falls on a third party (a child or partner) rather than the treated patient. (7)

Contraindications, precautions and interactions

Contraindications

• Combined hormonal contraceptives: personal history of deep vein thrombosis or pulmonary embolism, cerebrovascular or coronary artery disease, migraine with aura, uncontrolled hypertension, current or past breast cancer, thrombogenic heart valve or rhythm conditions, and known or suspected pregnancy. (1)
• Combined hormonal contraceptives are specifically contraindicated in women over 35 years old who smoke, reflecting the boxed warning on cardiovascular risk in that group. (1)
• Progestin-only methods (intrauterine system, implant, depot injection): known or suspected pregnancy, current or past breast cancer or other progestin-sensitive cancer, active liver disease or liver tumours, and undiagnosed abnormal genital bleeding. (3) (4) (2)
• The levonorgestrel intrauterine system is additionally contraindicated in acute pelvic inflammatory disease or a history of it (unless a subsequent intrauterine pregnancy has occurred), and in known uterine or cervical malignancy. (3)
• Menopausal hormone therapy: undiagnosed abnormal genital bleeding, current or past breast cancer, active or prior venous or arterial thromboembolic disease, known thrombophilic disorders, hepatic impairment, and known estrogen-dependent neoplasia. (5)
• Testosterone replacement is contraindicated in men with known or suspected breast or prostate carcinoma, and in pregnant or breastfeeding women because of the potential for fetal harm. (7)

Precautions

• Migraine with aura is treated as a strong caution or contraindication across estrogen-containing methods because of the associated stroke risk, and is specifically flagged in combined hormonal contraceptive labelling. (1)
• A family history of venous thromboembolism or a known thrombophilic mutation (such as factor V Leiden) is weighed carefully before starting any estrogen-containing method. (8)
• Adolescent or long-duration use of depot medroxyprogesterone acetate warrants specific bone-health counselling given the labelled uncertainty about peak bone mass and later fracture risk. (2)
• Starting menopausal hormone therapy well after menopause, or continuing it into older age, is part of the individualised discussion of cardiovascular and dementia risk described in the boxed warning. (6)

Drug interactions

• Enzyme-inducing drugs (e.g. certain anticonvulsants, rifampin): Can lower circulating levels of the contraceptive estrogen and progestin, reducing contraceptive reliability; a non-hormonal or alternative method is generally advised during concurrent use. (1)
• Other estrogen- or androgen-containing products: Concurrent use with another product supplying the same hormone class is generally avoided because it compounds dose-related risk rather than adding a therapeutic benefit. (5)

Comparison tables

High-yield exam pearls

• In combined hormonal contraceptives, the progestin does most of the ovulation-suppressing work; the estrogen mainly stabilises the endometrium for predictable bleeding, and it is the estrogen that drives the VTE signal. (8) (1) This is the reasoning that explains why progestin-only methods keep contraceptive efficacy while dropping the estrogen-linked boxed warning.
• The combined hormonal contraceptive boxed warning names women over 35 who smoke specifically, not smokers of any age. (1) Age and smoking status compound each other's cardiovascular risk in this population, which the label addresses as a defined subgroup rather than a general smoking warning.
• Depot medroxyprogesterone acetate's boxed warning is about bone, not clotting. (2) It is easy to assume every hormonal contraceptive shares the VTE warning; DMPA's defining labelled risk is bone mineral density loss instead, because it has no estrogen component.
• Unopposed estrogen needs a uterus to cause its signature harm. (5) The endometrial cancer risk from estrogen-alone therapy applies to women with an intact uterus; a woman without a uterus is typically offered estrogen alone precisely because that risk does not apply to her.
• Testosterone gel's boxed warning protects a third party, not the patient taking it. (7) Virilization from secondary exposure affects a child or partner who contacts the unwashed application site, which is a different kind of boxed warning from the direct-patient-risk warnings seen elsewhere in this class.

Common exam traps

• Trap: Assuming all hormonal contraceptives carry the same VTE boxed warning. Actually: The VTE warning belongs to estrogen-containing combined methods; progestin-only methods such as the intrauterine system, the implant and depot medroxyprogesterone acetate do not share it, though each has its own distinct labelled risk. (1) (2)
• Trap: Treating menopausal estrogen-alone and estrogen-plus-progestin therapy as interchangeable. Actually: Estrogen alone is reserved for a woman without a uterus because of the endometrial cancer risk of unopposed estrogen; a woman with an intact uterus needs the added progestin for endometrial protection. (5)
• Trap: Reading the combined hormonal contraceptive smoking warning as applying to any smoker. Actually: The labelled contraindication specifically targets women over 35 who smoke, reflecting the age-dependent compounding of cardiovascular risk rather than a blanket smoking contraindication at any age. (1)
• Trap: Assuming testosterone replacement is indicated for any man with a low testosterone level on a lab report. Actually: The labelled indication is confirmed primary or hypogonadotropic hypogonadism with clinical features plus laboratory testing, not an isolated low result in an otherwise asymptomatic man. (7)

Self-test questions

Answers are hidden until you open them. These questions are written from this page's cited content and are for study only — they are not clinical guidance.

1. Which component of a combined hormonal contraceptive is primarily responsible for suppressing ovulation?

   • Estrogen
   • Progestin
   • Neither hormone affects ovulation
   • Only the placebo-week tablets
   Show answer

   Answer: Progestin

   The progestin component is primarily responsible for inhibiting gonadotropin release and preventing ovulation, while the estrogen component mainly stabilises the endometrium for predictable bleeding. (8)

2. The boxed warning restricting combined hormonal contraceptive use specifically applies to which group?

   • Any woman with migraine
   • Women over 35 years old who smoke
   • All women over age 40
   • Women using the method for more than 5 years
   Show answer

   Answer: Women over 35 years old who smoke

   The labelling contraindicates combined hormonal contraceptive use in women over 35 who smoke because of sharply increased serious cardiovascular event risk in that specific combination of age and smoking. (1)

3. What is the signature boxed-warning risk of depot medroxyprogesterone acetate that is not shared with combined oral contraceptives?

   • Venous thromboembolism
   • Loss of bone mineral density with prolonged use
   • Endometrial cancer
   • Virilization of a partner
   Show answer

   Answer: Loss of bone mineral density with prolonged use

   Depot medroxyprogesterone acetate's own boxed warning covers bone mineral density loss that increases with duration of use and may not be fully reversible, distinct from the estrogen-driven VTE warning on combined methods. (2)

4. Why is a progestin added to estrogen therapy for a postmenopausal woman with an intact uterus?

   • To reduce hot flashes further
   • To protect the endometrium from unopposed estrogen's proliferative effect and reduce endometrial cancer risk
   • To reduce the estrogen dose needed
   • It has no additional purpose beyond estrogen alone
   Show answer

   Answer: To protect the endometrium from unopposed estrogen's proliferative effect and reduce endometrial cancer risk

   Unopposed estrogen in a woman with a uterus raises endometrial cancer risk roughly two to twelve-fold; adding a progestin counteracts that proliferative effect, which is the reason combined menopausal hormone therapy exists as a distinct product from estrogen alone. (5)

5. According to the Women's Health Initiative findings referenced in the Prempro/Premphase label, which outcome was increased with combined estrogen-plus-progestin therapy?

   • Only endometrial cancer
   • Stroke, DVT, pulmonary embolism, myocardial infarction, invasive breast cancer, and probable dementia in women 65 and older
   • Only bone fracture reduction
   • No cardiovascular outcomes were affected
   Show answer

   Answer: Stroke, DVT, pulmonary embolism, myocardial infarction, invasive breast cancer, and probable dementia in women 65 and older

   The Women's Health Initiative estrogen-plus-progestin substudy found increased stroke, venous thromboembolism, myocardial infarction and invasive breast cancer, and the associated Memory Study found increased probable dementia in women 65 and older. (6)

6. What does the boxed warning on topical testosterone gel primarily address?

   • Direct hepatotoxicity in the treated patient
   • Virilization in a child or partner from secondary skin contact with an unwashed application site
   • An increased risk of osteoporosis
   • A drug interaction with hormonal contraceptives
   Show answer

   Answer: Virilization in a child or partner from secondary skin contact with an unwashed application site

   The boxed warning concerns virilization from secondary exposure — a child or partner who contacts an unwashed application site can absorb enough testosterone to show signs of androgen exposure themselves. (7)

Frequently asked questions

References

1. YAZ (drospirenone and ethinyl estradiol) — prescribing information DailyMed, U.S. National Library of Medicine
2. DEPO-PROVERA CI (medroxyprogesterone acetate injectable suspension) — prescribing information DailyMed, U.S. National Library of Medicine
3. Mirena (levonorgestrel-releasing intrauterine system) — prescribing information DailyMed, U.S. National Library of Medicine
4. NEXPLANON (etonogestrel implant) — prescribing information DailyMed, U.S. National Library of Medicine
5. PREMARIN (conjugated estrogens) tablets — prescribing information DailyMed, U.S. National Library of Medicine
6. PREMPRO/PREMPHASE (conjugated estrogens/medroxyprogesterone acetate) — prescribing information DailyMed, U.S. National Library of Medicine
7. AndroGel (testosterone gel) — prescribing information DailyMed, U.S. National Library of Medicine
8. Oral Contraceptive Pills StatPearls Publishing / NCBI Bookshelf, 2024

Related drug classes

• Bisphosphonates and bone agents

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