Sex hormones and antihormones. Hormonal contraception – with lactation-focused notes.

General principles

Sex hormones are steroid compounds synthesized in the gonads, adrenal cortex and placenta; they control gametogenesis, secondary sexual characteristics, the menstrual cycle and pregnancy. Three major groups are distinguished: estrogens, progestagens (progesterone and synthetic analogues – progestins) and androgens. Antihormones include receptor antagonists, enzyme inhibitors and structural analogues with antagonistic effects at hormone receptors. Hormonal contraception uses combined estrogen–progestin or progestin-only regimens to prevent ovulation and/or implantation.

From a lactation perspective, high-dose estrogens may reduce milk volume, whereas progestin-only methods are preferred during breastfeeding because they have minimal impact on milk composition and supply when started after lactation is established (usually ≥6 weeks postpartum). Clinical guidelines generally recommend avoiding combined estrogen–progestin contraceptives in the early postpartum period, especially in mothers of preterm or medically fragile infants.

Estrogens

Physiological estrogens include estradiol (E2), the most potent estrogen in women of reproductive age, estrone (E1), dominant after menopause, and estriol (E3), predominant during pregnancy. Therapeutic and synthetic preparations include ethinylestradiol (EE), used orally in doses of 20–35 µg in combined hormonal contraceptives, with high bioavailability and a long half-life, as well as estradiol valerate and estradiol hemihydrate in oral, transdermal and vaginal forms. Estrogens act via ERα and ERβ receptors, increasing gene transcription and exerting tissue-specific agonist or antagonist-like effects (for example in bone and brain). Their main effects are proliferation of endometrium and breast tissue, antiresorptive action in bone, suppression of FSH/LH secretion, and increased thrombotic risk.

Indications include combined hormonal contraception, hormone replacement therapy, treatment of hypogonadism, osteoporosis and menopausal symptoms. Adverse effects are nausea, mastalgia, thromboembolism, cholestasis and tumor promotion in ER-positive cancers. Antiestrogens comprise tamoxifen (a selective estrogen receptor modulator acting as an antagonist in breast and agonist in bone and uterus, used for breast cancer therapy and prevention), fulvestrant (a pure ER antagonist given intramuscularly for ER-positive metastatic breast cancer), and aromatase inhibitors such as anastrozole and letrozole, which block peripheral estrogen synthesis and are used mainly postmenopausally in breast cancer.

In breastfeeding women, systemic estrogen exposure can reduce milk volume, particularly in the early postpartum period, and may theoretically alter prolactin dynamics, so estrogen-containing contraceptives are usually deferred until at least 6 months postpartum or avoided altogether if high breastfeeding intensity is desired. Vaginal or transdermal estradiol used for severe hypoestrogenic symptoms should be individually assessed, balancing maternal benefit against possible modest effects on lactation; infant exposure through milk is low but not negligible.

Progestagens (progesterone and progestins)

Natural progesterone has a short half-life and is available as injectable formulations (progesterone in oil 50–100 mg intramuscularly) and vaginal pessaries 100–400 mg. Synthetic progestins are grouped by “generations”: first-generation such as norethisterone and levonorgestrel with an androgenic residual activity; second-generation including desogestrel and gestodene with less androgenic effect; third-generation such as drospirenone with antimineralocorticoid and antiandrogenic properties; and fourth-generation agents like dienogest and newer drospirenone formulations with specific indications, for example endometriosis.

Progestagens act via PR-A and PR-B receptors, inducing secretory transformation of the endometrium, increasing cervical mucus viscosity and suppressing LH surge and ovulation. Indications include combined hormonal contraception, hormone replacement therapy, luteal support in IVF cycles, treatment of endometriosis, amenorrhea and premenstrual syndrome. Adverse effects may include acne, weight gain, depressive symptoms, amenorrhea, thrombotic events and cholestasis, with risk varying by progestin type and dose. Antiprogestins include mifepristone, a progesterone receptor antagonist used for medical abortion (200–600 mg combined with a prostaglandin), and ulipristal acetate, a selective progesterone receptor modulator (SPRM) indicated for uterine fibroids and emergency contraception.

From the standpoint of lactation, natural progesterone and most progestins are considered compatible with breastfeeding, with low levels in breast milk and no demonstrated clinically significant adverse effects on the breastfed infant when standard contraceptive doses are used. Progestin-only contraception (oral “mini-pill”, implants, intrauterine systems or injectable depots) is the method of choice for breastfeeding women, with typical recommendations to start from 3–6 weeks postpartum depending on clinical context and national guidelines. However, long-acting depot medroxyprogesterone acetate may modestly affect return to fertility and could be associated with maternal bone mineral density loss, which is relevant in undernourished breastfeeding women or those with other osteoporosis risk factors.

Androgens and antiandrogens

The main natural androgen is testosterone, the key male sex hormone with pronounced anabolic effects. Synthetic derivatives include methyltestosterone and fluoxymesterone orally, depot preparations such as testosterone enanthate or cypionate intramuscularly, testosterone undecanoate given orally or intramuscularly, and transdermal patches or gels. Indications cover male hypogonadism, delayed pubertal development, male osteoporosis, wasting syndromes in HIV, and gender-affirming hormone therapy in trans men. Adverse effects include polycythemia, acne, gynecomastia, hepatotoxicity for 17-alkylated oral forms, prostate hyperplasia and increased cardiovascular risk.

Antiandrogens comprise finasteride and dutasteride, 5α-reductase inhibitors used for benign prostatic hyperplasia and androgenetic alopecia, spironolactone as a mineralocorticoid receptor and androgen receptor antagonist used in acne and hirsutism, and non-steroidal AR antagonists such as bicalutamide and flutamide indicated in prostate cancer. In breastfeeding, therapeutic use of testosterone in a lactating mother is uncommon and generally contraindicated because of potential virilizing effects, milk suppression and possible impact on the infant’s hormonal milieu. Antiandrogens like finasteride and dutasteride are usually avoided in breastfeeding due to theoretical risks for the infant, particularly male fetuses or newborns, while spironolactone is considered lower risk but still requires careful individual evaluation.

Hormonal contraception

Combined oral contraceptives (COCs)

Combined oral contraceptives contain ethinylestradiol plus a progestin in 21/7 or 24/4 regimens, with EE doses of 20–35 µg. Progestin components reflect different “generations”, from first-generation levonorgestrel to newer agents such as drospirenone in fourth-generation formulations. Their mechanism involves central suppression of ovulation through enhanced negative feedback on the hypothalamic–pituitary–ovarian axis, reduced LH/FSH, increased cervical mucus viscosity and endometrial atrophy. Contraceptive efficacy is very high: with perfect use, failure rates are below 0.3%, while typical-use failure is around 7–9% per year.

Additional benefits include cycle regulation, reduced risk of endometrial and ovarian cancer, decreased incidence of ovarian cysts and improvement of acne. Adverse effects are thromboembolism, myocardial infarction, migraine, cholestasis, mastalgia and mood changes. Contraindications include prior thrombosis, smoking in women older than 35 years, migraine with aura, ER-positive tumors and significant liver disease. For breastfeeding women, COCs are generally not recommended before 6 months postpartum and often deferred until weaning because of the combined thrombotic risk in the postpartum period and the potential estrogen-related reduction in milk production. When used later in lactation, infant exposure through breast milk is low, but mothers should be counseled about possible small changes in milk volume and the need to monitor infant growth.

Progestin-only methods

Progestin-only methods include:

• The “mini-pill” (for example desogestrel 75 µg) taken continuously every 24 hours without breaks, suitable for breastfeeding women and those with thrombophilia.
• Depot injection: medroxyprogesterone acetate 150 mg intramuscularly every 3 months, with efficacy around 99% but adverse effects such as bone mass loss and weight gain.
• Subdermal implant: etonogestrel 68 mg placed subcutaneously for 3 years.
• Intrauterine system: levonorgestrel 52 mg (such as Mirena) providing 5 years of contraception through local progestin release and reduced menstrual bleeding.

For lactating women, progestin-only pills, implants and LNG intrauterine systems are considered first-line, as they do not significantly affect milk composition or infant growth and can usually be initiated from 3–6 weeks postpartum depending on maternal risk profile. Depot medroxyprogesterone acetate is also widely used in breastfeeding, but potential effects on maternal bone health should be taken into account, especially in women with pre-existing osteopenia or prolonged lactation with low dietary calcium intake. Mothers should be advised to maintain adequate calcium and vitamin D intake and weight-bearing exercise where feasible.

Emergency contraception

Emergency contraception options include levonorgestrel 1.5 mg orally within 72 hours after unprotected intercourse, with efficacy around 85%, and ulipristal acetate 30 mg up to 120 hours, with efficacy approximately 98%. Both act mainly by delaying or inhibiting ovulation when given before the LH surge. In breastfeeding, levonorgestrel is compatible with continued nursing; milk levels are low and no interruption of breastfeeding is required. For ulipristal acetate, some guidelines recommend discarding breast milk for 24 hours after administration because of theoretical concerns about infant exposure, although available data suggest a low risk; counseling should reflect current national or international recommendations and maternal preference.

Transdermal patch and vaginal ring

The transdermal contraceptive patch contains ethinylestradiol plus norelgestromin and is applied weekly, with efficacy similar to that of combined oral contraceptives. The vaginal contraceptive ring delivers ethinylestradiol and etonogestrel locally; it is worn for 3 weeks followed by a ring-free week and can reduce dysmenorrhea. Both methods are estrogen-containing and therefore share the same lactation-related concerns as COCs, namely potential reduction of milk supply and increased thrombotic risk in the early postpartum period. For breastfeeding women, they are usually reserved for later stages of lactation or used after weaning, and alternative progestin-only options are preferred when maintaining full breastfeeding is a priority.

Drug interactions and practical advice

Enzyme-inducing drugs such as rifampicin, carbamazepine and St. John’s wort lower serum levels of ethinylestradiol and progestins, decreasing contraceptive efficacy and necessitating additional barrier protection or alternative methods during and shortly after use of the inducer. Some antibiotics (for example penicillins and macrolides) have a theoretical impact on the enterohepatic circulation of ethinylestradiol, but clinically significant interactions are mainly documented with rifampicin. For breastfeeding women, the combination of enzyme-inducing antiepileptics or anti-infectives with hormonal contraception requires careful selection of contraceptive method (often progestin-only injectables or devices with high efficacy independent of systemic hormone levels) and individualized counseling. Documentation of all medicines used by the nursing mother and monitoring of both contraceptive success and infant growth are essential components of safe care.