Progestins General Statement (Monograph)

Drug class: Progestins
- Progestogens
ATC class: G03FA04
VA class: HS800

Introduction

Progestins elicit, to varying degrees, all the pharmacologic responses usually produced by progesterone.

Uses for Progestins General Statement

Progesterone is used to support embryo implantation and early pregnancy by supplementing corpus luteal function as part of assisted reproductive technology (ART) treatment of infertile women.

Progestins are used in the treatment of functional uterine bleeding caused by hormonal imbalance and involving a hyperplastic nonsecretory endometrium and the absence of underlying organic pathology such as fibroids or uterine cancer, and for the treatment of primary and secondary amenorrhea in the presence of estrogen. Medroxyprogesterone also is used in the adjunctive and palliative treatment of some cancers. (See the individual monographs in 68:32.) Some progestins are used alone or in combination with estrogens for the prevention of conception. Medroxyprogesterone prevents follicular maturation and ovulation following IM administration, and the drug has been used parenterally for contraception.

Progestins (e.g., drospirenone, medroxyprogesterone, norethindrone acetate, norgestimate, progesterone) are used to reduce the incidence of endometrial hyperplasia and the attendant risk of endometrial carcinoma in postmenopausal women receiving estrogen replacement therapy. Morphologic and biochemical studies of the endometrium suggest that 10–13 days of progestin are needed to provide maximum maturation of the endometrium and to eliminate any hyperplastic changes.

Although progestins have been used beginning in the first trimester of pregnancy to prevent habitual abortion or to treat threatened abortion, there is no adequate evidence from well-controlled studies to substantiate the efficacy of progestins for these uses; however, there is evidence of potential adverse effects on the fetus when these drugs are administered during the first 4 months of pregnancy. (See Cautions: Pregnancy and Lactation.) Although some progestins were previously used to induce withdrawal bleeding as a test for pregnancy when laboratory tests were not readily available, progestins are currently contraindicated for this use.

Cautions for Progestins General Statement

Adverse Effects

Progestins may cause breakthrough bleeding, spotting, changes in menstrual flow, amenorrhea, changes in cervical erosion and secretions, edema, weight gain or loss, nausea, cholestatic jaundice, allergic rash with or without pruritus, anaphylactoid reactions and anaphylaxis, melasma or chloasma, pyrexia, somnolence or insomnia, and mental depression.

An association between pulmonary embolism and cerebral thrombosis and embolism and use of estrogen-progestin combination preparations has been shown. The possibility that thromboembolic disorders may occur in patients receiving progestins should be considered and patients should be carefully observed for these effects during therapy with the drugs.

Although available evidence suggests that an association exists between neuro-ocular lesions such as optic neuritis or retinal thrombosis and use of estrogen-progestin combination preparations, such a relationship has been neither confirmed nor refuted. Increased blood pressure in susceptible individuals, premenstrual-like syndrome, changes in libido or appetite, cystitis-like syndrome, headache, nervousness, dizziness, fatigue, backache, hirsutism, loss of scalp hair, erythema multiforme or nodosum, hemorrhagic skin eruption, and itching have occurred in patients receiving estrogen-progestin combination preparations. Use of estrogen-progestin combinations has also been associated with increased levels of coagulation factors VII, VIII, IX, and X. The possibility that these effects may occur in patients receiving progestins should be considered and patients should be carefully observed for these effects during therapy with the drugs.

Because drospirenone has antimineralocorticoid activity, the potential exists for hyperkalemia to occur in high-risk patients (e.g., those with renal or hepatic impairment, adrenal insufficiency) receiving this progestin.

Precautions and Contraindications

Because oral contraceptive combinations contain progestins, the precautions associated with oral contraceptives should generally be considered in patients receiving progestins. Prior to initiation of therapy with progestins in women, a physical examination should be performed, including special attention to the breasts and pelvic organs and a Papanicolaou test (Pap smear). Women receiving progestins should be given a copy of the patient labeling for the drugs.

Progestins should be used with caution, and only with careful monitoring, in patients with conditions that might be aggravated by fluid retention (e.g., asthma, seizure disorders, migraine, or cardiac or renal dysfunction). Progestins should also be used with caution in patients with a history of mental depression; the drugs should be discontinued if depression recurs to a serious degree during progestin therapy.

When breakthrough bleeding or irregular vaginal bleeding occurs during progestin therapy, nonfunctional causes should be considered. Adequate diagnostic procedures should be performed in patients with undiagnosed vaginal bleeding.

The effect of long-term progestin therapy on pituitary, ovarian, adrenal, hepatic, or uterine function has not been determined. Diabetic patients should be carefully monitored during progestin therapy, since decreased glucose tolerance has been observed in women receiving estrogen-progestin combinations. Progestins may mask the onset of climacteric in women.

The clinician and the patient using progestins should be alert to the earliest signs and symptoms of thromboembolic and thrombotic disorders (e.g., thrombophlebitis, pulmonary embolism, cerebrovascular insufficiency, coronary occlusion, retinal thrombosis, mesenteric thrombosis). Progestins should be discontinued immediately when any of these disorders occurs or is suspected.

A safety review conducted by the US Food and Drug Administration (FDA) indicates that use of combination oral contraceptives containing the progestin drospirenone may be associated with an increased risk of venous thromboembolism (VTE) compared with that of oral contraceptives containing levonorgestrel or other progestins.^{201 202 210 211 212 213 214 219} This conclusion was based on results of several epidemiologic studies evaluating the risk of VTE in women using oral contraceptives containing drospirenone.^{201 202 205 206 207 208 209} These studies reported that the risk of VTE in such women ranged from no increase to a threefold increase in risk.^{203 204 205 206 207 208 211 212 213 214 215 217 218 219} The FDA’s safety review was prompted by results of 2 recent case-control studies that showed a twofold to threefold increased risk of VTE (including deep-vein thrombosis and pulmonary embolism) in patients receiving oral contraceptives containing drospirenone compared with those receiving oral contraceptives containing the progestin levonorgestrel.^{201 202 203 204 219} These studies evaluated cases of idiopathic VTE occurring in women 15–44 years of age who were current users of oral contraceptives containing 30 mcg of estrogen with either drospirenone or levonorgestrel; women with risk factors for VTE were excluded from the studies.^{203 204} The FDA has also reviewed data from a large US retrospective cohort study in more than 800,000 women evaluating thrombotic and thromboembolic risks (including VTE) associated with hormonal contraceptives.^{201 202 210 215} Final results from this study suggest an increased risk of VTE (hazard ratio greater than 1) in women using oral contraceptives containing drospirenone compared with women using other hormonal contraceptives.^{202 215}

Given the conflicting results of the previous epidemiologic studies and the recent findings, the FDA held a joint meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee on December 8, 2011, to review the risks and benefits of such therapy and specifically to discuss the risk of VTE associated with drospirenone-containing hormonal contraceptives.^{202 219} The studies reviewed by the FDA did not provide consistent data for the comparative risk of thromboembolic events between oral contraceptives that contain drospirenone and those that do not.²¹⁹ In addition, the studies did not account for important known and unknown patient characteristics that may influence prescribing patterns and may affect risk of VTE.²¹⁹ For these reasons, the FDA states that it is unclear whether the increased risk of thromboembolic events observed in these epidemiologic studies actually resulted from use of drospirenone-containing oral contraceptives.²¹⁹ At this time, the FDA has concluded that the risk of VTE may be higher for such oral contraceptives and will continue to communicate any new safety information as it becomes available.²¹⁹

Oral contraceptive combinations containing drospirenone should be discontinued if an arterial or venous thrombotic event occurs during therapy.^{211 212 213 214} The risk of VTE is highest during the first year of oral contraceptive use.^{211 212 213 214 219} Results from a large, prospective cohort safety study of various estrogen-progestin oral contraceptives suggest that this increased risk is highest during the first 6 months of use compared with that in nonusers.^{211 212 213 214} Data from this safety study indicate that the highest risk of VTE occurs after initiation of estrogen-progestin oral contraceptive therapy or resumption of therapy (following a 4-week or longer drug-free interval) with the same or a different oral contraceptive combination.^{211 212 213 214} Before initiating use of an estrogen-progestin combination containing drospirenone in a new user or in a woman who is switching from an oral contraceptive not containing drospirenone, clinicians should consider the risks and benefits of drospirenone-containing oral contraceptives, including risk for developing VTE, specific to that woman.^{202 210 211 212 213 214 219}

Women currently receiving an oral contraceptive combination containing drospirenone should be informed of the potential risk of thromboembolic events.^{202 219} Patients also should be advised about the current information available regarding the risk of VTE with oral contraceptives containing drospirenone compared with those containing levonorgestrel.²⁰² Patients should contact a clinician if they experience any signs or symptoms of VTE (e.g., persistent leg pain, severe chest pain, sudden shortness of breath).^{201 202 219} Known risk factors for development of VTE include smoking, obesity, family history, and other factors that contraindicate the use of oral contraceptive combinations.^{202 211 212 213 214} Patients should discuss their risk of VTE with their clinician before deciding which contraceptive method or hormonal contraceptive to use.^{202 210} The risk of thromboembolic disease associated with oral contraceptive use gradually disappears after such therapy is discontinued.^{211 212 213 214} However, the FDA states that patients should not discontinue oral contraceptives containing drospirenone without consulting a clinician.^{201 202 219}

If unexplained, sudden or gradual, partial or complete loss of vision; proptosis or diplopia; papilledema; retinal vascular lesions; or migraine occur during therapy with progestins, the drugs should be discontinued and appropriate diagnostic and therapeutic measures instituted. Because steroidal hormones are metabolized in the liver, progestins should be used with caution in patients with impaired liver function.

Drospirenone should not be used in patients who are predisposed to developing hyperkalemia (e.g., those with renal or hepatic impairment or adrenal insufficiency). If drospirenone is used in women receiving daily, long-term therapy with agents that may increase serum potassium concentrations (e.g., angiotensin-converting enzyme (ACE) inhibitors, angiotensin II type 1 (AT₁) receptor antagonists, potassium-sparing diuretics, potassium supplements, heparin, aldosterone antagonists [spironolactone], nonsteroidal anti-inflammatory agents [NSAIAs]), the serum potassium concentration should be determined during the first treatment cycle.

Progestins are contraindicated in patients with thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or a history of these conditions. The drugs are also contraindicated in patients with undiagnosed vaginal bleeding, missed abortion, known sensitivity to the drug or any ingredient in the formulation, markedly impaired liver function or liver disease, or carcinoma of the breast or for use as a pregnancy test.

Mutagenicity and Carcinogenicity

The carcinogenic and mutagenic potentials of progestins have not been fully determined.

Administration of medroxyprogesterone to beagles has been associated with the development of mammary nodules, some of which were malignant. Although nodules occasionally occurred in control beagles, they were intermittent in nature; nodules in drug-treated beagles were larger, more numerous, persistent, and occasionally malignant with metastases. The clinical relevance of these findings to humans has not been established.

Pregnancy and Lactation

Pregnancy

Progesterone is used to support embryo implantation and maintain pregnancy as a component of assisted reproductive technology (ART) treatment in infertile women. Such use is associated with increased ongoing pregnancy rates.

Although progestins have been used beginning in the first trimester of pregnancy to prevent habitual abortion or to treat threatened abortion, there is no adequate evidence from well-controlled studies to substantiate the efficacy of progestins for these uses; however, there is evidence of potential adverse effects on the fetus when these drugs are administered during the first 4 months of pregnancy. In addition, in most women, the cause of abortion is a defective ovum, which progestins could not be expected to influence. Because of their uterine-relaxant effects, progestins may delay spontaneous abortion of fertilized defective ova. Masculinization of the female fetus has reportedly occurred when progestins were used during pregnancy. Clitoral hypertrophy and fusion of the labia have been reported in a few female neonates born to women who had received medroxyprogesterone during pregnancy; hypospadias in male neonates born to women receiving progestational agents occurs at approximately twice the rate of occurrence in male neonates born to women not receiving the drugs. An association between intrauterine exposure to female sex hormones and congenital anomalies, including cardiovascular and limb defects, has been suggested. Use of progestins generally is not recommended during the first 4 months of pregnancy. If a woman becomes pregnant while receiving progestins or is inadvertently exposed to the drugs during the first 4 months of pregnancy, she should be advised of the potential risks to the fetus.

Progestins should not be used to induce withdrawal bleeding as a test for pregnancy.

Lactation

Progestins are reportedly distributed into milk. The possible effects of progestins in milk on nursing infants have not been determined.

Laboratory Test Interferences

Estrogen-progestin combinations have caused abnormal thyroid function test results. Estrogen-progestin combinations have altered the metyrapone test and liver function test results. These combinations have also caused decreased pregnanediol excretion.

The pathologist should be advised of progestin use when relevant specimens from a patient exposed to the drug are submitted.

Pharmacology

Progestins elicit, to varying degrees, all the pharmacologic responses usually produced by progesterone: induction of secretory changes in the endometrium, increase in basal body temperature (thermogenic action), production of histologic changes in vaginal epithelium, relaxation of uterine smooth muscle, stimulation of mammary alveolar tissue growth, pituitary inhibition, and production of withdrawal bleeding in the presence of estrogen.

Chemistry

The use of progesterone, a hormone secreted by the corpus luteum, is well established in medicine. Its relative inactivity following oral administration and the local reactions and pain sometimes produced upon injection have led to the synthesis of chemical derivatives that are effective orally, are more potent, more specific in action, or have a longer duration of action.

Ethisterone was the first synthetic progestin developed; the drug is not currently available. 19-Nor,17-acetoxy, and 6-methyl derivatives, which exhibit interesting structural-pharmacologic relationships, have been synthesized. Some estrogenic or androgenic activity, anabolic effects, nitrogen retention, and weight gain are exhibited by the 19-nor derivatives. The 17-hydroxy or acetoxy compounds, on the other hand, elicit responses more nearly resembling those of progesterone. They have little or no estrogenic or androgenic activity and may produce catabolic and slight diuretic effects. The 19-nor derivatives are more effective in postponing the normal menstrual period.

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