Megestrol acetate

Source: Wikipedia, the free encyclopedia.

Megestrol acetate
Clinical data
Trade namesMegace, others
Other namesMGA; BDH-1298; NSC-71423; SC-10363; 17α-Acetoxy-6-dehydro-6-methylprogesterone; 17α-Acetoxy-6-methylpregna-4,6-diene-3,20-dione
License data
Progestin; Progestogen ester; Antigonadotropin; Steroidal antiandrogen
ATC code
Legal status
Legal status
conjugation)[6]
Elimination half-lifeMean: 34 hours[5]
Range: 13–105 hours[5]
ExcretionUrine: 57–78%[6]
Feces: 8–30%[6]
Identifiers
  • [(8R,9S,10R,13S,14S,17R)-17-acetyl-6,10,13-trimethyl-3-oxo-2,8,9,11,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-17-yl] acetate
JSmol)
  • CC1=C[C@@H]2[C@H](CC[C@]3([C@H]2CC[C@@]3(C(=O)C)OC(=O)C)C)[C@@]4(C1=CC(=O)CC4)C
  • InChI=1S/C24H32O4/c1-14-12-18-19(22(4)9-6-17(27)13-21(14)22)7-10-23(5)20(18)8-11-24(23,15(2)25)28-16(3)26/h12-13,18-20H,6-11H2,1-5H3/t18-,19+,20+,22-,23+,24+/m1/s1
  • Key:RQZAXGRLVPAYTJ-GQFGMJRRSA-N

Megestrol acetate (MGA), sold under the brand name Megace among others, is a

wasting syndromes such as cachexia.[2][5][7][1] It is also used to treat breast cancer and endometrial cancer, and has been used in birth control.[5][7][8][9] Megestrol acetate is generally formulated alone, although it has been combined with estrogens in birth control formulations.[10] It is usually taken by mouth.[2]

antigonadotropic effects.[7] The mechanism of action of the appetite stimulant effects of megestrol acetate is unknown.[11][12][13]

Megestrol acetate was discovered in 1959 and was introduced for medical use, specifically in

birth control pills, in 1963.[8][9][14] It may be considered a "first-generation" progestin.[15] The medication was withdrawn in some countries in 1970 due to concerns about mammary toxicity observed in dogs, but this turned out not to apply to humans.[16][17][18][19][20] Megestrol acetate was approved for the treatment of endometrial cancer in 1971 and wasting syndromes in 1993.[7][21] It is marketed widely throughout the world.[22][23] It is available as a generic medication.[24]

Medical uses

Megestrol acetate is used mainly as an

combined injectable contraceptive in combination with estradiol as well.[33]

Although it has not been approved for these uses, megestrol acetate has been studied and/or used

gynecological/menstrual disorders,[41][42] endometriosis,[43] endometrial hyperplasia,[44] ovarian cancer,[45][46][47][48] prostate cancer,[49][50][51][52][53][54][55] benign prostatic hyperplasia,[56][57] male breast cancer,[58] and precocious puberty.[6][7][59] Megestrol acetate can also be used to treat pattern hair loss in men, but its side effects generally make it unacceptable for this purpose.[60]

Appetite stimulation is achieved with megestrol acetate with oral dosages of 400 to 800 mg/day.[61] The optimal dosage with maximum effect for appetite stimulation has been determined to be 800 mg/day.[62]

Available forms

See also: Estradiol/megestrol acetate and Ethinylestradiol/megestrol acetate

Megestrol acetate is available as 5 mg, 20 mg, and 40 mg

combined injectable contraceptive in women.[33]

Contraindications

teratogen in animals and may have the potential to cause fetal harm, such as decreased fetal weight and feminization of male fetuses.[1]

Side effects

The most common

intrahepatic cholestasis, and meningiomas in association with high-dosage megestrol acetate have been published.[74][75][76][77] In older patients who take megestrol acetate, one in 23 will have an adverse event leading to death.[78]

Overdose

Megestrol acetate has been studied at very high dosages of as much as 1,600 mg/day with no serious

dialyzability.[1] However, due to its low solubility, it is thought that dialysis would not be useful for treating megestrol acetate overdose.[1]

Interactions

Interactions of megestrol acetate include significantly decreased exposure to indinavir, which may necessitate an increased dosage of the medication.[1] When megestrol acetate is co-administered with zidovudine and rifabutin, there is no significant change in exposure to these medications and no dosage adjustment is necessary.[1]

Pharmacology

Pharmacodynamics

Megestrol acetate has

antigonadotropic effects, weak partial androgenic activity, and weak glucocorticoid activity.[2][4][80]

Relative affinities (%) of megestrol acetate
Compound PRTooltip Progesterone receptor ARTooltip Androgen receptor ERTooltip Estrogen receptor GRTooltip Glucocorticoid receptor MRTooltip Mineralocorticoid receptor SHBGTooltip Sex hormone-binding globulin
CBG
Tooltip Corticosteroid binding globulin
Megestrol acetate 65 5 0 30 0 0 0
Notes: Values are percentages (%). Reference
CBGTooltip Corticosteroid-binding globulin. Sources:[2][4][80]

Progestogenic activity

Megestrol acetate is a

endometrial transformation dose of megestrol acetate is 50 mg per cycle.[82]

Parenteral potencies and durations of progestogens[a][b]
Compound Form Dose for specific uses (mg)[c] DOA[d]
TFD[e] POICD[f] CICD[g]
Algestone acetophenide Oil soln. - – 75–150 14–32 d
Gestonorone caproate Oil soln. 25–50 – – 8–13 d
Hydroxyprogest. acetate[h] Aq. susp. 350 – – 9–16 d
Hydroxyprogest. caproate Oil soln. 250–500[i] – 250–500 5–21 d
Medroxyprog. acetate Aq. susp. 50–100 150 25 14–50+ d
Megestrol acetate Aq. susp. - – 25 >14 d
Norethisterone enanthate Oil soln. 100–200 200 50 11–52 d
Progesterone Oil soln. 200[i] – – 2–6 d
Aq. soln. ? – – 1–2 d
Aq. susp. 50–200 – – 7–14 d
Notes and sources:
  1. ^ Sources: [83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101]
  2. subcutaneous injection
    .
  3. OID
    Tooltip ovulation-inhibiting dose of OHPC is 250 to 500 mg/month.
  4. ^ Duration of action in days.
  5. ^ Usually given for 14 days.
  6. ^ Usually dosed every two to three months.
  7. ^ Usually dosed once monthly.
  8. ^ Never marketed or approved by this route.
  9. ^ a b In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4).

Antigonadotropic and anticorticotropic effects

Megestrol acetate has

negative feedback inhibition, and hence downregulates the hypothalamic–pituitary–gonadal axis (HPG axis), resulting in decreased levels of the sex hormones and interference with fertility.[106] As such, megestrol acetate has functional antiandrogenic and antiestrogenic effects as well as contraceptive effects via its antigonadotropic effects.[7]

The precise

birth control pills in combination with the estrogen ethinylestradiol or mestranol.[8][9][32] Megestrol acetate is an effective contraceptive by itself at dosages of 0.35 to 0.5 mg/day, but is not effective at a dosage of 0.25 mg/day.[7] Megestrol acetate alone does not inhibit ovulation at a dosage of 0.5 mg/day, nor does it fully inhibit ovulation at a dosage of 0.7 mg/day or even at a dosage of 5 mg/day.[7][41][108] The combination of 2 to 5 mg/day megestrol acetate and 100 μg/day mestranol has been found to consistently inhibit ovulation, whereas either medication alone did not completely inhibit ovulation in all women.[41][109]

Suppression of testosterone levels by megestrol acetate is responsible for its effectiveness in the treatment of conditions like prostate cancer and benign prostatic hyperplasia.

high-dosage estrogen monotherapy in the treatment of prostate cancer with comparatively greatly reduced toxicity and side effects.[7][25][52][53][111][114][115][116][117] In spite of these results, however, this combination has been very rarely used to treat prostate cancer in the United States.[111]

The antigonadotropic as well as

sex steroids and by extension circulating levels of estrogens, by about 80%.[118][119][120]

Androgenic and antiandrogenic activity

Megestrol acetate is a weak

LDL cholesterol levels and no change in triglyceride levels at a dosage of only 5 mg/day.[2] Conversely, megestrol acetate does not decrease sex hormone-binding globulin levels.[126] The weak but significant androgenic activity of megestrol acetate may serve to limit its clinical effectiveness in the treatment of prostate cancer.[122][123][127][128]

Glucocorticoid activity

Megestrol acetate is an agonist of the

hyperglycemic activity (markers of glucocorticoid activity) of an equal amount of medroxyprogesterone acetate and about 25% that of hydrocortisone.[129] Accordingly, manifestations of its glucocorticoid activity, including symptoms of Cushing's syndrome, steroid diabetes, and adrenal insufficiency, have been reported with the use of megestrol acetate in the literature, albeit sporadically.[71]

Appetite stimulation

Megestrol acetate is frequently used as an

anabolic effects.[131] Studies of megestrol acetate in elderly patients who experience weight loss are limited and of poor quality with most showing minimal or no weight gain, with no nutritional or clinically significant beneficial outcomes observed. In patients who take megestrol acetate, one in 12 will have an increase in weight.[78]

Miscellaneous

Unlike the case of the androgen receptor, megestrol acetate has no significant affinity for the estrogen receptor.

antimineralocorticoid activity.[2][4][80]

Megestrol acetate has been found to dose-dependently increase total and free IGF-1 levels up to a dosage of 120 mg/day.

anabolic effects of megestrol acetate in patients with cachexia.[131]

Pharmacokinetics

The

excreted 57 to 78% in urine and 8 to 30% in feces.[6]

At high doses, megestrol acetate appears to have far greater bioavailability and

resistance to metabolism of megestrol acetate afforded by its C6(7) double bond (medroxyprogesterone acetate being identical to megestrol acetate in structure except lacking this feature).[6][138][139]

The pharmacokinetics of megestrol acetate have been reviewed.[2][82][140]

Chemistry

See also: List of progestogens, Progestogen ester, List of progestogen esters, Steroidal antiandrogen, and List of steroidal antiandrogens

Megestrol acetate, also known as 17α-acetoxy-6-dehydro-6-methylprogesterone or as 17α-acetoxy-6-methylpregna-4,6-diene-3,20-dione, is a

Analogues of megestrol acetate include other 17α-hydroxyprogesterone derivatives such as acetomepregenol, anagestone acetate, chlormadinone acetate, cyproterone acetate, hydroxyprogesterone caproate, medroxyprogesterone acetate, and nomegestrol acetate.[22][141] Megestrol acetate differs from medroxyprogesterone acetate only by its C6(7) double bond.[142] Close analogues of megestrol acetate that were never marketed include cymegesolate (megestrol acetate 3β-cypionate) and megestrol caproate.[143][144][145]

Synthesis

Chemical syntheses of megestrol acetate have been published.[146][147]

History

Megestrol acetate was

British Drug Houses in the United Kingdom under the brand name Volidan (4 mg MGA and 50 μg EE tablets),[8][9] and this was followed by Serial 28 (1 mg MGA and 100 μg EE tablets) and Volidan 21 (4 mg MGA and 50 μg EE tablets) in 1964 and Nuvacon (2 mg MGA and 100 μg EE tablets) in 1967, all by British Drug Houses also in the United Kingdom.[32] It was also marketed under the brand name Delpregnin (5 mg MGA and 100 μg mestranol tablets) by 1965, among others.[136][148][149][150] Megestrol acetate-containing birth control pills were withdrawn after reports in the early 1970s of a high incidence of venous thromboembolism with the preparations.[126]

In the early 1970s, megestrol acetate was found to be associated with mammary tumors in beagle dogs, and along with several other progestogens, was withdrawn as an oral contraceptive from several markets including the United Kingdom, Canada, and West Germany.[16][17][18] It was also under investigation for use as a contraceptive in the United States, but development was discontinued in 1972 following the mammary toxicity findings in dogs, and megestrol acetate was never marketed as an oral contraceptive in the United States.[18][19][151] Subsequent research, such as monkey studies, revealed that there is no similar risk in humans.[6][20] Following its withdrawal from the market, megestrol acetate was eventually reintroduced for the treatment of hormone-sensitive cancers.[151] In addition, megestrol acetate was marketed for veterinary use in dogs in 1969 in the United Kingdom and in 1974 in the United States.[152][153][154]

Progesterone was first found to be effective in the treatment of endometrial hyperplasia in 1951,[6] and progestins were first found to be effective in the treatment of endometrial cancer in 1959.[155] Megestrol acetate was reported to be effective in the treatment of endometrial hyperplasia in the mid-1960s.[6] It first started to be studied as a treatment for endometrial cancer in 1967, with findings published in 1973.[6][156][157] Megestrol acetate was reportedly introduced for the treatment of endometrial cancer in the United States in 1971.[7] Progesterone was studied in the treatment of breast cancer in 1951 and 1952, but with relatively modest results.[158][159][160] Megestrol acetate was first studied in the treatment of breast cancer in 1967, and was one of the first progestins to be evaluated for the treatment of this disease.[6][30][161] A second study was conducted in 1974.[6][162] A "breakthrough" and surge of interest in progestins for breast cancer occurred in 1978 when a study using a massive dosage of medroxyprogesterone acetate to treat breast cancer was published.[158][163] A third study of megestrol acetate for breast cancer was published in 1980, and this was followed by additional studies in the 1980s and beyond.[6][164][165] Megestrol acetate was approved for the treatment of breast cancer in the United States by at least 1983.[6]

Progestogens, including progesterone and ethisterone, were studied in the treatment prostate cancer in 1949.[6][166] Megestrol acetate was first studied in the treatment of prostate cancer in 1970.[6][167] Additional studies were conducted in 1975 and 1978, followed by others thereafter.[6][7][50][54] However, results of megestrol acetate therapy for prostate cancer have been "disappointing",[168] and the medication has not been approved for the treatment of prostate cancer in the United States or elsewhere.[111]

Clinical studies of very high dosages of megestrol acetate for breast cancer conducted in the 1980s observed markedly increased appetite and weight gain in treated patients despite them having advanced cancer.

Par Pharmaceutical, for treatment of unintentional weight loss in elderly patients, especially those living in long-term care facilities. In March 2013, Par settled a $45 million federal and multi-state criminal and civil lawsuit in which the company was accused of promoting the branded version of megestrol acetate, over the generic version, for use in treating non-AIDS-related geriatric wasting. This use was not approved as safe and effective by the Food and Drug Administration (FDA), and not covered by federal health care programs. The lawsuit claimed that Par marketed the product as effective for this use, despite having conducted no well-controlled studies to support a claim of greater efficacy for Megace ES, and prior knowledge of the severe adverse side effects for geriatric patients, including deep vein thrombosis, toxic reactions with impaired renal function, and mortality.[175]

Society and culture

Generic names

Megestrol acetate is the

INNTooltip International Nonproprietary Name and BANTooltip British Approved Name and mégestrol the DCFTooltip Dénomination Commune Française of megestrol, the free alcohol form of megestrol acetate.[10][22][23][141] The medication is also known by its developmental code names BDH-1298, NSC-71423, and SC-10363.[10][22][23][141]

Brand names

Megestrol acetate is marketed under a variety of brand names throughout the world but is most commonly sold under the brand name Megace.[22][23][141] It is also available under the brand name Megace ES in the United States and under the brand name Megace OS in Canada.[23] For use in veterinary medicine, megestrol acetate is sold as Ovaban in the United States and as Ovarid in the United Kingdom.[23]

In Bangladesh and India, megestrol is marketed under the brand name Megestol by Ziska Pharmaceuticals, Mezest by Beacon Pharmaceuticals, and under the trade name Varigestrol by Laboratorio Varifarma, Argentina.

Availability

See also: List of progestogens available in the United States

Megestrol acetate is available widely throughout the world, including in the United States, Canada, the United Kingdom, Ireland, elsewhere throughout Europe, Australia, New Zealand, Latin America, Asia, and a few African countries.[22][23]

Generation

Progestins in birth control pills are sometimes grouped by generation.

19-nortestosterone progestins are consistently grouped into generations, the pregnane progestins that are or have been used in birth control pills are typically omitted from such classifications or are grouped simply as "miscellaneous" or "pregnanes".[176][177] In any case, based on its date of introduction in such formulations of 1963, megestrol acetate could be considered a "first-generation" progestin.[15]

Research

Megestrol acetate has been studied in men in combination with testosterone as a male hormonal contraceptive to suppress spermatogenesis.[7][178]

Veterinary use

Megestrol acetate has been used in

urine spraying, and roaming in male dogs and cats.[180][181]

See also

References

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    . Specific actions of neurosteroids on ion transport across the neuronal plasma membrane have been described (see Fig. 2[10). In hippocampal CA1 neurons, Ffrench Mullen et al. (76) observed an inhibition by PREG, PREGS, and 3α,5β-TH PROG (but not PROG) of both the N- and L-type calcium channel currents, mediated by a pertussis toxin-sensitive G protein mechanism, associated with the activation of protein kinase C. PROG still has no effect on calcium channels of hypothalamic neurons from the ventromedial nucleus; however, the synthetic progestin megestrol acetate inhibits some high-threshold Ca2+ channel currents: not the N-type nor the P-type Ca2+ channel currents, but the residual current. Appetite enhancement induced by megestrol acetate might be partly due to the inhibition of these Ca2+ channel currents, and the attenuation of the firing of ventromedial nucleus neurons, involved in satiety mechanisms (77).
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Further reading