Megestrol is a progestin, a modified derivative of the naturally occurring female hormone progesterone, indicated primarily to stimulate appetite for the treatment of significant, inexplicable weight loss in HIV/AIDS patients and anorexia or cachexia syndrome. Approved by the FDA in 1971, the drug induces a non-fluid weight gain by specifically increasing body fat and not muscle mass. The medication, however, does not result in complete weight loss recovery. It is also administered for the palliative treatment of advanced endometrial cancer and breast cancer as a second or third-line agent of therapy.[1][2]

Megestrol has been studied heavily for various off-label uses such as anorexia-cachexia syndrome in cancer patients, endometriosis, ovarian cancer, and advanced prostate cancer. Low dose megestrol has shown to reduce the frequency of hot flashes in menopausal women and in men who have received androgen suppression therapy for prostate cancer. It has also been proposed as an alternative treatment for endometrial hyperplasia without atypia. The drug has also been used for the management of geriatric wasting syndrome by improving appetite, elevating prealbumin and albumin levels, and increasing weight. Current studies are investigating the efficacy of megestrol in the treatment of inoperable hepatocellular carcinoma in increasing survival rate and reducing tumor size.[3][4][5]

Megestrol is a synthetic form of progesterone. The mechanism of action has not been fully elucidated in terms of distinguishing its various functions, such as appetite stimulant and antineoplastic agent. It functions as an agonist with a higher affinity to the progesterone receptor than progesterone. There is also a suggestion that megestrol is a glucocorticoid agonist. One study revealed that megestrol binds more strongly than cortisol, the primary naturally occurring ligand, to glucocorticoid receptors with a 46% affinity when compared to cortisol’s 25% affinity. This mechanism has correlated with long-term-use adverse effects such as steroid diabetes and Cushing-like symptoms.[6][7]

Megestrol also possesses anti-gonadotropic activity as a downstream effect of the activation of the progesterone receptor by reducing overall natural steroid synthesis. This action includes inducing suppression of luteinizing hormone and estrogen release from the anterior pituitary gland and has thus linked to megestrol’s application against breast and endometrial cancer. A proposed theory about the management of prostate cancer suggests megestrol blocks gonadotropins by inhibiting 5-alpha reductase and thus reducing dihydrotestosterone levels. Overall, megestrol likely suppresses the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis.[8][9][10]

Another hypothesis about the mechanism of action of megestrol is that it inhibits the in vitro production of cytokines such as tumor necrosis factor- α, interleukin-1, and interleukin-6 and thus contributes to the orexigenic and weight gain effects of megestrol. The weight gain effect has also been proposed to be mediated by increased Neuropeptide Y synthesis, transport, and release. CYP3A4 may also metabolize megestrol, so it is important to monitor this prescription with other CYP3A4 substrates.[11][12][13]

Two approved forms of administration exist for megestrol: tablet form and concentrated oral suspension form. A newly synthesized nanocrystal oral suspension form is currently under investigation for improving bioavailability in the fasting state and optimize bioavailability and delivery. The tablet form is available as a 20 mg or 40 mg tablet, while the concentrated oral suspension form is available at 40 mg/1mL or a more concentrated form of 125 mg/1mL. The 40 mg oral tablet is usually prescribed four times a day as a starting dosage until a maximum dosage of 800 mg, while the liquid form is prescribed for once-daily administration.

Literature has indicated that dosages can vary from 100 mg to 1600 mg/day for appetite stimulation. Megestrol demonstrates a positive dose-response effect for improving appetite. Megestrol is typically recommended for a minimum of six weeks. For the treatment of neoplastic disease, the dosage ranges from 480 to 600 mg/day. For endometrial cancer or atypical hyperplasia, the most common dosages were 160 to 400 mg per day. The initial adult dosage of the oral suspension form for HIV patients is 800 mg/day.[14][15][16][17]

The metabolism of megestrol is primarily hepatic by hydroxylation, reduction, and conjugation. Therefore, the dosage should be adjusted for patients with hepatic impairment as it can affect megestrol plasma concentrations. Megestrol is also significantly excreted by the kidney, so dosage adjustments are necessary for patients with impaired renal function.[18]

The most common side effects of megestrol are weight gain and an increase in appetite. Adverse effects include nausea, vomiting, rash, diarrhea, vaginal bleeding, edema, dyspnea, hypogonadism, hyperglycemia, fluid retention, loss of libido, and hypertension. A severe adverse effect is increased risk for venous thromboembolic events such as thrombophlebitis and deep venous thrombosis due to increase coagulopathy.

Another severe adverse effect is glucocorticoid side effects such as new-onset diabetes mellitus, worsening of pre-existing diabetes, Cushing-like symptoms, and symptoms of secondary adrenal insufficiency like hypotension, fatigue, and muscle weakness. It is necessary to evaluate the side effects of long-term use, which has links to the glucocorticoid side effects and sudden discontinuation of megestrol, which has demonstrated symptoms of adrenal gland suppression. If the patient and/or prescribing physician decides to discontinue the drug, the drug should be tapered off and not suddenly discontinued to minimize the risk of adverse side effects.[19][20][21][22][23]

Megestrol is categorized as a Category-X drug, making it an absolute contraindication during pregnancy. Women of childbearing age are recommended to use effective birth control and should notify the prescribing physician immediately if they become pregnant during treatment. Megestrol is also contraindicated during breastfeeding. A history of hypersensitivity to any components of the drug is also a contraindication. A history of thromboembolism, an active thromboembolic event, and a high risk for thromboembolism are relative contraindications. The Beers Criteria by the American Geriatrics Society designates megestrol as a potentially inappropriate medication for geriatric patients as it can increase the risk of venous thromboembolic disease.[24][25]