Professional Information

Progestins (Systemic)

This monograph includes information on the following:

1) Hydroxyprogesterone ^†
2) Levonorgestrel
3) Medrogestone ^*
4) Medroxyprogesterone
5) Megestrol
6) Norethindrone
7) Norgestrel ^†
8) Progesterone

Note: For information pertaining to the use of estrogens and progestins oral contraceptives, see Estrogens and Progestins Oral Contraceptives (Systemic) and for use of progesterone intrauterine device, see Progesterone Intrauterine Device (IUD).

INN:
Hydroxyprogesterone caproate—Hydroxyprogesterone
Medroxyprogesterone acetate—Medroxyprogesterone
Megestrol acetate—Megestrol
Norethindrone—Norethisterone

BAN:
Hydroxyprogesterone caproate—Hydroxyprogesterone
Medroxyprogesterone acetate—Medroxyprogesterone
Megestrol acetate—Megestrol
Norethindrone—Norethisterone

VA CLASSIFICATION
Hydroxyprogesterone
Primary: HS103

Levonorgestrel
Primary: HS103
Secondary: HS104

Medrogestone
Primary: HS103

Medroxyprogesterone
Primary: HS103
Secondary: AN500; HS104

Megestrol
Primary: HS103
Secondary: AN500

Norethindrone
Primary: HS103
Secondary: HS104

Norgestrel
Primary: HS103
Secondary: HS104

Progesterone
Primary: HS103

Commonly used brand name(s): Alti-MPA⁴; Amen⁴; Apo-Megestrol⁵; Aygestin⁶; Colprone³; Crinone⁸; Curretab⁴; Cycrin⁴; Depo-Provera⁴; Depo-Provera Contraceptive Injection⁴; Gen-Medroxy⁴; Gesterol 50⁸; Gesterol LA 250¹; Hy/Gestrone¹; Hylutin¹; Megace⁵; Megace OS⁵; Micronor⁶; NORPLANT System²; Nor-QD⁶; Norlutate⁶; Novo-Medrone⁴; Ovrette⁷; PMS-Progesterone⁸; Plan B²; Pro-Span¹; Prodrox¹; Prometrium⁸; Provera⁴; Provera Pak⁴.

Another commonly used name for norethindrone is
norethisterone .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^*Not commercially available in the U.S.

^†Not commercially available in Canada.

Category:

Progestational agent—Hydroxyprogesterone; Medrogestone; Medroxyprogesterone (oral); Norethindrone; Norgestrel; Progesterone;

Antianoretic—Megestrol;

Anticachectic—Megestrol;

Antineoplastic—Medroxyprogesterone (parenteral); Megestrol;

Contraceptive (systemic)—Levonorgestrel; Medroxyprogesterone (parenteral); Norethindrone (base); Norgestrel;

Diagnostic aid (estrogen production)—Hydroxyprogesterone; Medroxyprogesterone (oral); Progesterone (parenteral);

Infertility therapy adjunct—Progesterone (vaginal);

Ovarian hormone therapy agent adjunct—Medroxyprogesterone (oral); Progesterone (oral);

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Amenorrhea, secondary (treatment)
Dysfunctional uterine bleeding (treatment) or
Menses, induction of (treatment)—Hydroxyprogesterone, medrogestone, oral medroxyprogesterone, norethindrone acetate, and parenteral progesterone are indicated in the treatment of menstrual disorders ^{41} ^{74}, including secondary amenorrhea and dysfunctional uterine bleeding (DUB) caused by hormonal imbalance in the absence of organic pathology ^{59} ^{65} ^{69} ^{74} ^{80} ^{81} ^{82} ^{83} ^{97} ^{100}. Progesterone oral capsules¹ and progesterone vaginal gel are indicated in the treatment of secondary amenorrhea. The 8% strength of vaginal gel is used only if the patient fails to respond to treatment with the 4% progesterone vaginal gel ^{244}. Hydroxyprogesterone is also indicated for the production of a secretory endometrium and desquamation ^{97}. The uterus must be sufficiently primed with endogenous or exogenous estrogen for the progestins to produce a secretory-like endometrium and endometrial shedding after progestin use ends ^{22} ^{69} ^{97} ^{100} ^{229}. Withdrawal bleeding usually occurs 3 to 7 days after discontinuation of the progestin for women with an intact uterus. ^{74} ^{226}

Anorexia (treatment)
Cachexia (treatment) or
Weight loss, significant (treatment)— Megestrol suspension is indicated in the treatment of anorexia, cachexia, unexplained significant weight loss (loss of 10% or more of base-line body weight) associated with acquired immunodeficiency syndrome (AIDS) ^{66} ^{67} ^{166} ^{167}. [Megestrol tablets are indicated in the treatment of anorexia, cachexia, and unexplained significant weight loss associated with cancer] ^{67}.

Assisted reproductive technologies, in females or
[Corpus luteum insufficiency (treatment) ]¹—Progesterone vaginal gel is indicated to replace the progesterone hormone in female patients whose infertility is due to partial or complete ovarian failure. Progesterone vaginal gel is indicated to supplement endogenous progesterone for luteal phase progesterone deficiency. Extemporaneously prepared [progesterone suppositories]¹ have also been used for these indications. ^{244}

Carcinoma, breast (treatment)—Megestrol and [ oral and parenteral medroxyprogesterone] are indicated in the treatment of breast carcinoma; [medroxyprogesterone] is indicated for use in postmenopausal women only ^{67} ^{68} ^{73} ^{74} ^{139} ^{149} ^{151} ^{158} ^{159} ^{160} ^{161} ^{162} ^{176}. It is used as adjunctive or palliative therapy in the treatment of advanced (inoperable, recurrent, or metastatic) hormonally dependent carcinoma ^{67} ^{73}.

Carcinoma, endometrial (treatment) —[Oral] or parenteral medroxyprogesterone ^{10} ^{74} ^{202} ^{214}, and megestrol are indicated for the treatment of endometrial carcinoma ^{67} ^{68} ^{72} ^{73} ^{74} ^{154}. It is used as adjunctive and/or palliative therapy in the treatment of advanced (recurrent or metastatic) hormonally dependent carcinoma ^{67} ^{73}.

Carcinoma, prostate (treatment)—[ Megestrol] is indicated in the treatment of hormonally dependent and advanced prostate carcinoma as palliative therapy ^{67}.

Carcinoma, renal (treatment)—Parenteral medroxyprogesterone is also indicated in the treatment of metastatic renal carcinoma ^{72} ^{73} ^{172} ^{173} ^{182} as adjunctive and/or palliative therapy when used in the treatment of advanced (recurrent or metastatic) hormonally dependent carcinoma ^{67} ^{73}.

Contraception, emergency postcoital (prophylaxis)—Levonorgestrel, oral^{254}

Endometriosis (treatment)—Norethindrone acetate, [parenteral medroxyprogesterone], and [ oral medroxyprogesterone]¹ are indicated in the treatment of endometriosis ^{05} ^{65} ^{73} ^{82} ^{83} ^{186} ^{191}.

Estrogen production, endogenous ^{47} ^{48} ^{97} (diagnosis)—Hydroxyprogesterone, [oral medroxyprogesterone], and [ parenteral progesterone] are indicated as a test for endogenous estrogen production and can be used to determine whether low levels of estrogen are present if withdrawal bleeding does not occur after a progestin challenge in menopausal women before estrogen-progestin ovarian hormone therapy is considered. However, determination that serum gonadotropins are elevated is the standard way to confirm menopause. ^{47} ^{48} ^{97} ^{186} ^{229} ^{230} ^{231} ^{232} ^{234}

[Hyperplasia, endometrial (treatment)]¹ or
Hyperplasia, endometrial, estrogen-induced (prophylaxis)—Megestrol and oral medroxyprogesterone have been used to treat endometrial hyperplasia without atypia, which is usually not a precursor of carcinoma. Complex atypical hyperplasia (previously called adenomatous hyperplasia) is usually best treated surgically, but in some high risk patients or when future pregnancy is desired, high continuous doses of progestins have been used. ^{216} ^{217} ^{218} ^{219} ^{220} ^{236} ^{237}
—For prevention, [oral medroxyprogesterone], ^{186} [norethindrone]¹, medrogestone, and [oral progesterone] can be used to oppose the effects of estrogen on the endometrium in menopausal women ^{245} who take estrogens for ovarian hormone therapy (OHT), also called hormone replacement therapy (HRT) and estrogen replacement therapy (ERT). All menopausal patients receiving progestins do not have recognized endometrial shedding; there is frequently amenorrhea after several months of treatment with estrogen-progestin regimens. ^{189} ^{202} The optimal or recommended length for estrogen replacement after menopause has not been established. ^{17} ^{100} ^{165} ^{232} Studies have shown that administration of a progestin for a minimum of 10 to 14 ^{61} ^{165} days of an estrogen cycle in women with an intact uterus is required for major reduction of endometrial hyperplasia and endometrial carcinoma ^{12} ^{82} ^{155} ^{165} compared with an estrogen-only cycle. Other dosing regimens for estrogens and progestins, including low continuous daily dosing, are also used. ^{188} ^{189} ^{223} ^{224} Progestins without estrogens may be used for debilitating menopausal symptoms in patients who have breast cancer and are candidates for progestin therapy but cannot take estrogens. ^{187}

Pregnancy, prevention of—Levonorgestrel, parenteral medroxyprogesterone, norethindrone (base), and norgestrel are indicated for the prevention of pregnancy ^{57} ^{63} ^{71} ^{73} ^{84} ^{86} ^{88} ^{90} ^{96}. Progestin-only oral contraceptives are also called minipills and progestin-only oral pills (POPs) ^{249}.
—The following table presents the results of studies examining contraceptive failure rates calculated using the life-table method. The first column lists the contraceptive method used. The second column indicates the percentage of women experiencing an accidental pregnancy in the first year of use of a contraceptive method while using the method perfectly under clinical conditions. The range of failure rates in the clinical trials may be explained by interstudy variations in study design or patient population characteristics, such as motivation, fecundity, or socioeconomic factors (including education). The third column indicates contraceptive failure rates in the first year of contraceptive use under clinical conditions for typical couples who start using a method (not necessarily for the first time). Failure rates among adolescents may be higher due to poorer compliance than in other age groups. ^{53} ^{54} ^{55}

Method used		Failure rate range (over 12 months) in clinical studies (%)	Typical first year failure rate (%)
None		78–94	85
Spermicides ^*		0.3–37	21
Periodic abstinence ^†		13–35	20
Withdrawal		7–22	19
Cervical cap with spermicide		6–27	18
Diaphragm with spermicide		2–23	18
Condom without spermicide		2–14	12
IUD
Progesterone-releasing		1.9–2	2
Copper-T 200		3–3.6
Copper-T 200Ag ^‡		0–1.2
Copper-T 220C ^§		0.9–1.8
Copper-T 380A		0.5–0.8	0.8
Copper-T 380S ^{53} ^{54}		0.9
Oral contraceptive	3
Estrogen and progestin		0–6
Progestin only		1–10	0.5
Progestin injection
Medroxyprogesterone (90-day)		0–0.3	0.3
Levonorgestrel (subdermal)
Six implants		0–0.09	0.09
Two rods		0–0.2	0.3
Sterilization
Female ^#		0–8	0.4
Male		0–0.5	0.15

^* Spermicides studied include creams, foams, gels, jellies, and suppositories. ^{53} ^{54}
^† Methods studied include calendar, ovulation method, symptothermal (cervical mucus method supplemented by basal body temperature post-ovulation). ^{53} ^{54}
^‡ Life table method rate is unavailable for Copper-T 200Ag and the Pearl method rate at 12 months was reported; these methods at 12 months are considered comparable. ^{50} ^{51} ^{52}
^§ Copper-T 220C is manufactured with copper sleeves instead of copper wire; often used as a control in clinical studies. ^{55}
^# Methods studied include culdotomy laparoscopy, minilaparotomy, electrocoagulation, laparotomy, tubal diathermy and/or use of rings or clips. ^{53} ^{54}

[Polycystic ovary syndrome (treatment) ]¹—Medroxyprogesterone is used in the treatment of endometrial hyperplasia and its consequences in syndromes, such as polycystic ovary syndrome. ^{35} ^{122}

[Puberty, precocious (treatment)]¹—Parenteral medroxyprogesterone is accepted therapy for use in the treatment of precocious puberty but has been replaced by other treatment modalities. ^{35} ^{122}

Unaccepted
There is no evidence that progesterone is effective in the treatment of premenstrual syndrome. ^{04} ^{86} ^{178}

Progestins are no longer recommended for use as pregnancy tests because of possible teratogenic effects with synthetic progestins; also, other tests available are quicker and easier to perform. ^{67} ^{68} ^{69} ^{70} ^{71} ^{72} ^{73} ^{82}

With the exception of progesterone in patients who are progesterone deficient, progestins have no proven value in the treatment of threatened abortion and are no longer recommended for such use. ^{32} ^{39} ^{40} ^{66} ^{68} ^{69} ^{82}

Unlike oral medroxyprogesterone, parenteral medroxyprogesterone is not recommended by the manufacturer for treatment of secondary amenorrhea or dysfunctional uterine bleeding. ^{72} ^{73}

Megestrol is not recommended for prophylactic use to avoid weight loss. ^{66}

Levonorgestrel used for emergency postcoital contraception is not recommended for routine use as a contraceptive^{254}.

Levonorgestrel used for emergency postcoital contraception is not effective in terminating an existing pregnancy^{254}.

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Table 1. Pharmacokinetics

Drug	Protein ^* binding (%)	Biotransformation	Elimination half-life (hrs)	Time to peak concentration (hrs)	Peak serum concentration	Renal elimination (%)	Fecal elimination (%)
Drug	Protein ^* binding (%)	Biotransformation	Elimination half-life (hrs)	Time to peak concentration (hrs)	ng/mL	Renal elimination (%)	Fecal elimination (%)	Dose (mg)
Natural:
Progesterone ^{106} ^†	Very high (90% or more)	Hepatic	Several minutes, after absorption				50–60	10
Oral, micronized				2–4	24.3	200
IM				28	39.1	45
IM				19.6	53.8	90
Vaginal gel, micronized				55	13.2	45
Vaginal gel, micronized				34.8	14.9	45
Synthetic 17-hydroxy derivatives:
Hydroxyprogesterone caproate	Very high (90% or more)	Hepatic
Medroxyprogesterone acetate ^{74} ^{106} ^{107} ^{108}	Very high (90% or more)	Hepatic					15–22	45–80
Oral			30	Within 2–4	19–35	10
IM		No first-pass hepatic effect	50 days	3 weeks	1–7	150 ^‡
Medrogestone ^{100}			4	1
Megestrol acetate	Very high (90% or more)	Hepatic	38 (13–104)				66	20
Oral				2–3	200	160
Oral				2–3	753	600
Synthetic 19-nor derivatives:
Levonorgestrel subdermal implants ^{23} ^{106} ^{108}	Very high ^§ (90% or more)	No first-pass hepatic effect	16 (8–30)	24	1.6, within first week	216 ^**	45	32
3 months					0.4
12 months					0.32
60 months					0.26
Norgestrel ^{106} ^{107}	Very high (90% or more)		20
Norethindrone ^{23} ^{108}	Very high ^# (90% or more)	Hepatic first pass effect	8 (6–12)	2			50	20–40
Norethindrone acetate ^{23} ^{108}	Very high (90% or more)	Hepatic first pass effect	8

^* Sex hormone–binding globulin (SHBG) synthesis is stimulated by estrogens and inhibited by androgens; levels are twice as high in women as in men. ^{20} ^{42}
^† Progesterone binds strongly to cortisol binding globulin (CBG) 17.7%, SHBG 0.6%, and weakly to albumin 79.3% ^{15} ^{42}. Absorption is the rate-limiting step for the elimination half-life ^{244}.
^‡ Pertains to parenteral medroxyprogesterone for contraception injection formulation (150mg/mL) only given every 3 months. ^{188} ^{222}
^§ Levonorgestrel: Free, 1.1–1.7%; SHBG 92–62%; albumin 37.56%, but suppresses SHBG by 33%. ^{15} ^{20} ^{42} ^{104}
^# Norethindrone: Free 3.5%; SHBG 35.5%; albumin 61%. ^{108}
^** 216 mg is the loading dose for 6 levonorgestrel implants; a mean dose of 35 mcg levonorgestrel is released daily. ^{88}

Physicochemical characteristics:
Molecular weight—
    Hydroxyprogesterone caproate: 428.62 ^{75}
    Levonorgestrel: 312.45 ^{75}
    Medrogestone: 340.51 ^{75}
    Medroxyprogesterone acetate: 386.53 ^{75}
    Megestrol acetate: 384.52 ^{75}
    Norethindrone: 298.43 ^{75}
    Norethindrone acetate: 340.47 ^{75}
    Norgestrel: 312.45 ^{75}
    Progesterone: 314.47 ^{75}

Mechanism of action/Effect:

Progestins enter target cells by passive diffusion and bind to cytosolic (soluble) receptors that are loosely bound in the nucleus. The steroid receptor complex initiates transcription, resulting in an increase in protein synthesis.

Progestins are capable of affecting serum concentrations of other hormones, particularly estrogen. Estrogenic effects are modified by the progestins, either by reducing the availability or stability of the hormone receptor complex or by turning off specific hormone-responsive genes by direct interaction with the progestin receptor in the nucleus. ^{68} In addition, estrogen priming is necessary to increase progestin effects by upregulating the number of progestin receptors and/or increasing progesterone production, causing a negative feedback mechanism that inhibits estrogen receptors. ^{119}

Depending on the progestin and its dose, progestin may demonstrate varying degrees of progestational effects. Also, other hormonal effects, such as estrogenic-, ^{83} ^{90} ^{97} anabolic-, ^{67} ^{69} ^{74} ^{83} ^{90} ^{97} androgenic-, ^{67} ^{69} ^{74} ^{83} ^{90} ^{97} or glucocorticoid-inducing or suppressing ^{67} ^{74} ^{97} effects are demonstrated to different degrees and depend on the progestin type and dose. ^{33} ^{67} For example, an androgenic effect may be expressed by 19-nor derivatives of testosterone but not by other progestins. The androgenic effects of norethindrone are minor to moderate; norethindrone acetate is twice as potent as norethindrone. Norgestrel and levonorgestrel have androgenic effects if unopposed by estrogens. ^{33} ^{40} ^{221} ^{238} ^{239} Rare cases of adrenal suppression have been reported in patients using megestrol ^{67}. While the progestational effects dominate, the other effects can become important when choosing the appropriate progestin or monitoring side effects. Progestins are not used exclusively for other than their progestational effects, as the other effects are highly variable and unreliable.

Progestational agents—Progestins produce significant antiproliferative changes in the endometrium. ^{12} ^{100} As progestin levels fall after estrogen priming in the second half of the menstrual cycle, uterine bleeding may occur ^{226} ^{246}. Depending on the estrogen-progestin regimen, the progestin dose may be sufficient to cause amenorrhea ^{246}.

Antianoretic or anticachectic—The mechanism that produces weight gain has not been fully elucidated; ^{66} ^{110} ^{166} however, megestrol appears to have appetite-stimulant and metabolic effects that result in weight gain while causing minimal fluid retention. ^{110} ^{111} The underlying cause of wasting should be treated concurrently to optimize management of catabolism. ^{110} ^{166} ^{167}

Antineoplastic—The mechanism has not been fully elucidated; however, several mechanisms may be involved that are dependent on the type and dose of progestin. ^{115} ^{149} In certain doses, progestins can produce a diminished response to endogenous hormones in tumor cells by decreasing the number of steroid hormone receptors (estrogen, progesterone, androgen, and glucocorticoid); the degree of variation of response is tissue- and progestin-dependent. ^{150} ^{156} The suppression of the growth of hormone-sensitive cells may be due to a direct cytotoxic effect or antiproliferative effects on cell cycle growth and an increased terminal cell differentiation. ^{150} ^{154} ^{235} At higher doses, some progestins compete for the glucocorticoid receptor, resulting in suppressed adrenal production of estradiol and androstenedione. ^{150} ^{156} Still-higher progestin doses are able to completely suppress the hypothalamic-pituitary-adrenal axis (HPA axis), an effect that is important in the treatment of estrogen- or testosterone-sensitive tumors. ^{40} ^{115} ^{149} ^{152}

Contraceptive (systemic)—Inhibition of the secretion of gonadotropins from the anterior pituitary prevents ovulation and follicular maturation and is one of the contraceptive actions of levonorgestrel, parenteral medroxyprogesterone, norethindrone, ^{193} and norgestrel. These effects do not occur with low-dose oral medroxyprogesterone, which is not used for contraception. In some patients using low-dose progestin-only contraceptives, particularly norethindrone (base) and levonorgestrel subdermal implants, ovulation is not suppressed consistently from cycle to cycle. The contraceptive effect of the progestin is achieved through other mechanisms that result in interference with fertilization and implantation in the luteal cycle, such as thickening of the cervical mucus and changes in the endometrium ^{71} ^{81} ^{84} ^{86} ^{88} ^{90} ^{117} ^{118}. In males, medroxyprogesterone suppresses the Leydig cell function. ^{13} ^{74}

Other actions/effects:

Progestins increase body temperature, stimulate the respiratory center, and, in some cases, may provide pain relief. ^{156} ^{157} The mechanism by which progesterone and medroxyprogesterone mediate thermogenic effects is not clear. It has been suggested that progesterone influences neurotransmitters and neuropeptides in the brain, notably endogenous opioids, interleukin-1, and serotonin, ^{59} ^{81} ^{100} ^{119} that raise body temperature. ^{74} Also, medroxyprogesterone may reduce hypercapnia in certain patients by stimulating the respiratory center. ^{74} Pain relief from high-dose progestins may be due in part to an anti-inflammatory action. ^{34}

Locally the progestins relax the uterine smooth muscle, sustain pregnancy, decrease the immune response, and, acting with estrogen, stimulate breast tissue growth. ^{81}

Some progestins cause sodium and water retention. Progesterone doses of 50 to 100 mg may produce a moderate catabolic effect and transient increase in sodium chloride excretion. ^{59} In addition, use of some progestins may result in dose-related adverse effects on carbohydrate and lipid metabolism. ^{72} ^{97} ^{165}

Progestins influence bone density. When progestins have been used without estrogen, a positive effect has been shown in postmenopausal women and a possible negative effect in premenopausal women; the latter may depend on the degree to which a progestin can reduce ovarian estrogen production, a dose-dependent effect. When progestins have been used sequentially with continuously administered estrogen, a synergistic protective effect on bone density has been shown. Specifically, placebo-controlled studies of postmenopausal women showed that medroxyprogesterone decreased the rate of cortical bone loss but did not protect trabecular areas of the skeleton, such as the spine, equally from bone loss in all studies. ^{05} ^{06} ^{62} ^{103} ^{163} ^{164} ^{191} ^{192} A low-dose combination of continuously administered estrogen and sequentially administered progestin therapy showed protective effects against bone loss that were similar to those of higher doses of estrogen therapy alone. This effect may be due to an increase of progestin receptors caused by estrogen, to an antagonistic effect of progestin binding to glucocorticoid receptors, or to a stimulatory effect of progestin acting on progestin receptors within osteoblasts. ^{05} ^{06} ^{14} ^{62} ^{163} ^{164} ^{200} ^{210} Additional studies are needed to confirm and fully characterize these results. ^{188}

Other health benefits of progestational hormone therapy may include less painful menstruation, less menstrual blood loss and anemia, ^{14} ^{148} fewer pelvic infections, and lower incidence of uterine cancers. ^{12} ^{14} ^{90} ^{97} ^{155} ^{165} ^{177} ^{200}

Absorption:

Progestins—Well absorbed. ^{58} ^{59} ^{68} ^{80} ^{81} ^{100} ^{147} ^{238}

Levonorgestrel subdermal implants and parenteral medroxyprogesterone acetate—Well-absorbed during controlled release with wide intra- and intersubject variability. Initial release rate for a set of levonorgestrel subdermal implants is approximately 80 micrograms of levonorgestrel per 24 hours. This rate declines over the first 6 to 18 months to an approximately constant release rate of 30 micrograms of levonorgestrel per 24 hours over the remainder of the 5 years of use. ^{71} ^{88} ^{109} ^{133}

Progesterone—Micronized progesterone improves surface area contact and absorption compared to nonmicronized progesterone; both types have been used in extemporaneously prepared formulations. ^{245}

• Micronized progesterone, oral—Luteal phase concentrations of progesterone are maintained for approximately 9 to 12 hours after oral administration. Food significantly increases absorption as shown by increases in the area under the plasma concentration–time curve (AUC) and peak concentration, but the time to peak concentration is not affected. ^{245}

• Micronized progesterone, vaginal gel—Since the progesterone is soluble in both the water and oil phases, the vaginal gel (as an oil and water emulsion) provides a prolonged action and an absorption half-life of 25 to 50 hours ^{244}.

Precautions to Consider

Carcinogenicity

The benefit of lowering the incidence of endometrial hyperplasia and endometrial cancer by adding progestin to an estrogen regimen in ovarian hormone therapy to counter estrogen's effect on the uterus is established. ^{11} ^{12} ^{20} ^{22} ^{97} ^{100} ^{120} ^{155} ^{165}

Medroxyprogesterone:

Long-term studies in humans using parenteral medroxyprogesterone for contraception have found no increase in the overall risk of ovarian, liver, breast, or cervical cancer and have found a prolonged, protective effect of reducing the risk of endometrial cancer ^{11} ^{12} ^{123} for at least 8 years. ^{11} The possible protective effect may be lessened with concomitant use of estrogen; however, the lifetime risk for developing endometrial cancer is not increased in women with a uterus who take estrogen plus a progestin for 10 to 20 years. ^{22} ^{61} In the short-term, the initial risk of breast cancer with parenteral medroxyprogesterone exposure may be increased in the first 4 years after initial exposure in women under 35 years of age. The risk lessens with duration of use and results in no overall increase of risk for developing breast cancer. ^{11}

Studies of monkeys administered doses of 3, 30, and 150 mg per kg (mg/kg) of body weight every 90 days for 10 years produced undifferentiated carcinoma of the uterus in a few monkeys dosed at 150 mg/kg. No uterine malignancies were reported in monkeys taking other doses or in the control monkeys; no uterine abnormalities were produced in similar studies of rats after 2 years. ^{74} The relevance of these findings to humans is not known.

Tumorigenicity

Tumorigenicity/Mutagenicity

Hydroxyprogesterone, levonorgestrel, medrogestone, norgestrel, norethindrone, and progesterone

Studies have not been done ^{59} ^{65} ^{80} ^{81} ^{85} ^{86} ^{88} ^{90} ^{96} ^{97} ^{100}.

Medroxyprogesterone

Studies in humans have not been done ^{69} ^{70} ^{71} ^{72} ^{73} ^{74} ^{76} ^{77} ^{78} ^{79}.

Mammary nodules, some of which were malignant in the high-dose group, developed in a number of beagles given doses of 3 or 75 mg/kg of medroxyprogesterone every 90 days for 7 years ^{74}. In studies of monkeys, doses of 3, 30, or 150 mg/kg of medroxyprogesterone given every 90 days for 10 years produced transient mammary nodules in the 3 and 30 mg/kg groups, with none reported in the 150 mg/kg group during the study; hyperplastic nodules had developed in 3 monkeys that had been administered 30 mg/kg of medroxyprogesterone; no breast abnormalities were produced in rats after 2 years ^{74}. Caution is warranted in applying these results of animal studies of progestins to their use in humans because of the hormonal differences between species. Also, humans and beagles metabolize medroxyprogesterone differently, and beagles are particularly susceptible to this type of breast tumor and develop these tumors spontaneously without progestin use. ^{36} ^{49} ^{123} ^{201}

There was no mutagenic response in the Ames and micronucleus tests ^{69} ^{74}.

Megestrol

Studies in humans have not been done ^{67} ^{68}.

Studies of female dogs given megestrol for up to 7 years showed an increased incidence of both benign and malignant tumors; 2-year studies of female rats demonstrated an increased incidence of pituitary tumors. These effects were not found in monkey studies. ^{66} ^{68}

Pregnancy/Reproduction
Fertility—
Progestins cause a decrease in quantity and/or change the quality of cervical mucus and may interfere with sperm function, fertilization, and subsequently, the occurrence of pregnancy. This effect depends on the dose and type of the progestin. High-dose or long-term use of progestins may cause a delayed return to fertility. ^{69} ^{72} ^{74} ^{83} ^{90} ^{194}

Levonorgestrel subdermal implants

After removal, 40% of those women wanting to conceive did so by 3 months; 76% conceived within 1 year, percentages are similar to normal pregnancy rates. ^{133} ^{138}

Medroxyprogesterone

It has been reported that of the women who discontinued parenteral medroxyprogesterone to become pregnant, 68% conceived within 12 months, 83% conceived within 15 months, and 93% conceived within 18 months after discontinuation (range, 4 to 31 months; median 10 months). ^{36} ^{71} The return of fertility is a function of the uptake and metabolism of parenteral medroxyprogesterone; follicular activity has been reported to return 3 to 37 days after parenteral medroxyprogesterone is nondetectable in serum, whereas, luteal function is delayed by 14 to 102 days. ^{37} ^{38} ^{71}

Animal studies with medroxyprogesterone have reported no impairment of fertility in first- or second-generation studies. ^{74}

Megestrol

Studies in humans have not been done. ^{66}

Studies of rats given megestrol in doses of 0.05 to 12.5 mg per kg of body weight (mg/kg), which are lower than the human dose of 13.3 mg/kg, resulted in impaired reproductive capability of male offspring produced from megestrol-treated females; similar results were found in studies of dogs. ^{66}

Progesterone

Progesterone has been used successfully with assisted reproductive technologies to support embryo implantation and to maintain pregnancy if needed. ^{194} ^{195}

Pregnancy—
Progestins, in general, should be withheld during pregnancy. ^{202} Progestins cross the placenta. Although many studies fail to demonstrate an increase in teratogenicity when progestins are given in the first trimester, the possibility that genital abnormalities may appear in male and female fetuses exposed to progestins during that period has been suggested by some studies. The low number of abnormalities reported include an increased risk of hypospadias in male fetuses exposed to intrauterine progesterone and virilization of the female fetus' external genitalia when exposed to ethisterone and norethindrone. ^{39} There is some controversy about the reliability of these reports. The significant concentration of endogenous natural progesterone produced during pregnancy is devoid of teratogenic effects. ^{02} ^{21} ^{24} ^{25} ^{26} ^{27} ^{28} ^{29} ^{30} ^{31} ^{39} ^{59}

Ectopic pregnancy is possible with contraception failure because some progestin-only contraceptives reduce ectopic pregnancy risk substantially, but prevent ectopic pregnancy less effectively than intrauterine pregnancy. ^{71} ^{90} ^{232} For progestin-only oral contraceptives, the ectopic pregnancy rate reported is 4.1 per 100 pregnancies. ^{177} The rate of ectopic pregnancy for a set of levonorgestrel subdermal implants is 1.3 per 1000 woman-years. This is lower than those for women not using any contraceptive method (2.7 to 3 ectopic pregnancies per 1000 woman-years). However, the risk may increase with longer duration of use of levonorgestrel subdermal implants and increased weight of the user; risk does not increase in women of normal weight. ^{88} ^{138} ^{148} ^{194}

Hydroxyprogesterone and progesterone

Use is generally not recommended during pregnancy, unless prescribed in the treatment of female infertility due to progesterone deficiency. Hydroxyprogesterone and progesterone have been used to prevent habitual or threatened abortion within the first few months of pregnancy. There are no adequate and well-controlled studies in humans to document that such use is effective during the first 4 months of pregnancy in preventing miscarriage; use is generally limited to certain cases of hormonal imbalance. Progesterone has been used successfully with assisted reproductive technologies to support embryo implantation and maintain pregnancy. ^{194} ^{195} Progesterone may be used to treat corpus luteum deficiency in early pregnancy. Progesterone replacement or supplementation does not appear to be efficacious when a hormone imbalance does not exist. ^{194} In addition, the progesterone's effects on the uterus may delay the spontaneous miscarriage of a defective ovum. ^{02} ^{03} ^{32} ^{58} ^{80} ^{81} ^{97}

FDA Pregnancy Category D. ^{97}

Levonorgestrel, norethindrone, and norgestrel

Use is not recommended during pregnancy. Virilization of the female fetus has been reported with norethindrone in a few cases, but a causal relationship has not been conclusively proven. ^{88}

FDA Pregnancy Category X. ^{82} ^{86} ^{88} ^{90} ^{96}

Medroxyprogesterone

Use is not recommended in pregnancy. Studies in humans have shown that medroxyprogesterone may decrease intrauterine growth. ^{194} Polysyndactyly in the offspring of women who had used parenteral medroxyprogesterone during pregnancy was reported in a few case-reports; this effect has not been seen in major studies. ^{71} ^{195} Furthermore, there has been no evidence of problems associated with growth and development in children exposed in utero to medroxyprogesterone and followed to adolescence. ^{71}

In studies of pregnant beagles given doses of 1, 10, and 30 mg/kg of body weight per day for 6 months, clitoral hypertrophy appeared in the female pups of the high-dose group; no abnormalities were reported in the male pups. No abnormalities were detected in the treated female pups' offspring. Caution is warranted in transferring this information to humans because beagle dogs metabolize medroxyprogesterone differently than do humans. ^{74} ^{238}

Medroxyprogesterone, parenteral—FDA Pregnancy Category X. ^{71} ^{74} ^{97}

Note: An FDA pregnancy category has not been assigned for medroxyprogesterone tablets.

Megestrol

Use is not recommended during pregnancy. Risk-benefit must be carefully considered. ^{66} ^{67} ^{68}

Studies in pregnant rats given high doses of megestrol decreased fetal birth weight, produced fewer live births, and resulted in reversible feminization of some male fetuses. ^{66} ^{68}

Megestrol suspension—FDA Pregnancy Category X. ^{66}

Megestrol tablets—FDA Pregnancy Category D. ^{68}

Breast-feeding

Progestins are distributed into breast milk in variable amounts and, depending on the progestin and dose, may increase or decrease quantity or quality or have no effect on breast milk. ^{141} ^{142} The effect on the nursing infant has not been determined for many progestins.

No adverse effects on breast milk's quantity or quality ^{71} ^{84} ^{88} ^{141} ^{142} ^{143} ^{144} ^{145} ^{177} have been seen with progestin-only contraceptives, ^{195} ^{211} ^{212} or specifically, when norethindrone or medroxyprogesterone was used for contraception within 5 days postpartum or after the establishment of lactation. ^{14} ^{84} Progestin-only contraceptives are recommended in breast-feeding women when oral contraception is desired. The manufacturers and distributors of levonorgestrel subdermal implants and parenteral medroxyprogesterone for contraception recommend that their initial use for contraception begin at 6 weeks postpartum for exclusively breast-feeding mothers. ^{88} ^{70} ^{188} ^{212} Additionally, no adverse effects have been reported in a study of ^{71} ^{84} ^{141} nursing infants exposed to parenteral medroxyprogesterone and followed through puberty or in another study of 80 nursing infants exposed to levonorgestrel subdermal implants 6 weeks after delivery and followed for 3 years. ^{71} ^{88} ^{141} ^{212}

Progestins used in very high doses are not recommended for use by nursing mothers. ^{58} ^{59} ^{66} ^{68} ^{69} ^{71} ^{72} ^{73} ^{74} ^{80} ^{81} ^{82} ^{86} ^{90} ^{96} ^{99} ^{100}

Pediatrics

No information is available on the relationship of age to the effects of progestins in pediatric patients. Safety and efficacy have not been established. ^{59} ^{66} ^{68} ^{82} ^{97} Serious adverse effects have not been reported in small children who ingested large doses of oral contraceptives. ^{90} ^{148}

Adolescents

Safety and efficacy of progestin-only contraceptives are expected to be the same in postpubertal adolescents as they are in adults. However, special counseling for medication compliance and prevention of sexually transmitted diseases (STDs) is needed. Studies have shown that adolescents tend to have a higher failure rate with the use of any type of contraceptive that requires strict compliance, such as oral progestins for contraception, and its use is not generally recommended in this age group. ^{189} Although parenteral medroxyprogesterone and levonorgestrel subdermal implants do not require daily compliance, readministration of their doses after 3 months (13 weeks) and after 5 years, respectively, is important. Furthermore, none of the progestin contraceptives protect against STDs, which are significant risk-factors for this age group. ^{45} ^{46}

Geriatrics

No information is available on the relationship of age to the effects of progestins in geriatric patients. ^{59} ^{97}

Dental

Increased concentrations of progestins increase the normal oral flora growth rate, leading to an increase in inflammation of the gingival tissues and increased bleeding. A strictly enforced program of teeth cleaning by a professional, combined with plaque control by the patient, will minimize severity. ^{124} ^{125}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Aminoglutethimide    (may significantly lower the serum concentrations of oral and parenteral ^{186} ^{188} medroxyprogesterone by an undetermined mechanism; it has been suggested that aminoglutethimide may decrease the intestinal absorption of oral medroxyprogesterone ^{69} ^{71} ^{72} ^{73} ^{74} ^{126} ^{127})

» Hepatic enzyme inducing medications, such as
Carbamazepine or
Phenobarbital or
Phenytoin or
Rifabutin or^{197}^{198}
Rifampin    (decreased efficacy of some progestins, including levonorgestrel subdermal implants, has been suggested to be caused by enhanced metabolism of the progestins by these drugs ^{84} ^{86} ^{88} ^{90} ^{121} ^{128} ^{129} ^{147} ^{183})

    (phenytoin and rifampin increase the serum concentrations of sex hormone–binding globulin [SHBG]; this significantly decreases the serum concentration of free drug for some progestins ^{84} ^{86} ^{88} ^{90} ^{121} ^{128} ^{129} ^{147} ^{199}, which is a special concern in patients using progestins for contraception)

    (drug interaction data are not available for rifabutin, but because its structure is similar to that of rifampin, similar precautions with its use with progestins may be warranted. Megestrol has been shown not to affect the pharmacokinetics of rifabutin; whether rifabutin changes megestrol pharmacokinetics has not been studied ^{67} ^{197} ^{198})

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Biopsy    (pathologist should be notified of relevant specimens ^{66} ^{72} ^{73} ^{74} ^{82} ^{86})

Glucose tolerance test^{59}^{72}^{73}^{74}^{82}^{86}^{90}^{131}^{137}    (varies with progestin and dose, glucose tolerance may be increased or decreased)

Metyrapone^{59}^{73}^{74}^{82}^{97}    (lower response than normally expected)

With laboratory test values
Apolipoprotein A and
High-density lipoproteins (HDL) and
Total cholesterol and
Triglycerides    (serum concentrations may be increased or decreased and may differ depending on type of progestin, dose, dosing, and duration of therapy. In general, all progestins will lower triglyceride and total cholesterol concentrations. Parenteral medroxyprogesterone, in low doses, produces no significant decrease in HDL cholesterol concentrations; oral doses may blunt an estrogen-induced increase of HDL. In contrast, 19-nor-testosterone–derived progestins significantly lower HDL cholesterol as well as total cholesterol ^{14} ^{16} ^{17} ^{18} ^{19} ^{90} ^{130} ^{137} ^{163} ^{194} ^{200})

Apolipoprotein B and
Low-density lipoproteins (LDL)^{14}^{71}^{72}^{86}^{88}^{90}^{130}^{137}^{148}    (serum concentrations may be increased and may differ depending on type of progestin, dose, dosing, and duration of therapy ^{16} ^{17} ^{18} ^{19} ^{130})

    (LDL concentrations increased initially in some studies and then returned to normal or below normal baseline levels when progestins were given for a year. Additionally, serum estrogen concentrations seemed to influence the cyclicality and degree to which LDL concentration increased; progestins affected the values to a lesser extent when estrogen levels were normal ^{16} ^{17} ^{18} ^{19} ^{60})

Clotting factors II, VII, VIII, IX, and X and^{59}^{81}^{97}^{105}^{130}
Prothrombin^{81}^{105}    (serum concentrations may be increased although studies have not shown consistent results; no change in clotting factors has been reported with parenteral medroxyprogesterone for contraception ^{43} ^{71} ^{72} ^{81} ^{82} ^{86} ^{90} ^{130} ^{188})

Gonadotropin and^{188}
Sex hormone–binding globulin (SHBG)    (serum concentration may be decreased ^{20} ^{71} ^{72} ^{74} ^{86} ^{88} ^{90} ^{133})

Liver function tests^{71}^{72}^{73}^{74}^{81}^{82}^{86}^{97}    (values may be increased; if abnormal with parenteral medroxyprogesterone use, liver tests may be repeated 4 to 6 months after its discontinuation ^{59} ^{71} ^{72} ^{73})

T₃-uptake    (values may be decreased because of increase in thyroid-binding globulin [TBG]; free T₄ concentration is unaltered ^{59} ^{71} ^{72} ^{81} ^{82} ^{86} ^{90} ^{97})

T₄, total    (unaffected by most progestins but concentrations are slightly decreased with levonorgestrel; free T₄ concentration is unaltered ^{88} ^{133} ^{197})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, these medications should not be used when the following medical problems exist:
» Allergy to peanuts for oral or parenteral progesterone^{245}
» Breast malignancies or tumors, known or suspected^{59}^{72}^{73}^{74}^{81}^{83}^{86}^{188}^{197}    (may worsen conditions in some nonresponsive patients; however, some progestins are used for palliative treatment in select patients ^{11} ^{68} ^{71} ^{73} ^{86} ^{88})

» Hepatic disease, acute, including benign or malignant liver tumors    (metabolism of 19-nor derivatives of testosterone-type progestins may be impaired; also, progestins may worsen the condition ^{81} ^{88} ^{200})

Hypersensitivity to progestins^{72}^{73}^{74}^{83}^{86}^{245}
» Pregnancy, known or suspected^{81}    (use of synthetic progestins during pregnancy may result in virilization of a female fetus and, in a small number of cases, increase the risk of hypospadias in a male fetus ^{29} ^{30} ^{32} ^{59})

    (use for pregnancy diagnosis is contraindicated ^{59} ^{66} ^{68} ^{71} ^{72} ^{73} ^{74} ^{81} ^{83} ^{86} ^{88})

» Thrombophlebitis or thromboembolic disease, active    (the large doses of progestins used to treat breast and prostate cancer have been associated with a slight risk of thrombogenic conditions; mechanism is unclear and may be due to underlying condition. Problems have not been associated with low doses used for contraception, including parenteral medroxyprogesterone, progestin-only oral contraceptives, and levonorgestrel subdermal implants ^{66} ^{71} ^{72} ^{73} ^{74} ^{82} ^{86} ^{88} ^{90} ^{105} ^{111} ^{123} ^{130} ^{132} ^{135} ^{190})

» Urinary tract bleeding, undiagnosed or^{59}^{72}^{74}^{81}
» Uterine or genital bleeding, undiagnosed    (use of a progestin may delay diagnosis by masking underlying conditions, including cancer ^{72} ^{73} ^{74} ^{81} ^{83} ^{86} ^{88} ^{100} ^{202})

Risk-benefit should be considered when the following medical problems exist
Asthma or
Cardiac insufficiency, significant or
Epilepsy or
Hypertension or
Migraine headaches or
Renal dysfunction, significant    (fluid retention may be caused by some progestins, especially in high doses, and may aggravate these conditions ^{59} ^{71} ^{73} ^{74} ^{81} ^{82} ^{86} ^{88} ^{90} ^{100})

CNS disorders, such as depression or convulsions, history of    (progestins, such as levonorgestrel, medroxyprogesterone, or norethindrone, may make these conditions worse. Cases of convulsions have been reported with use of parenteral medroxyprogesterone; however, a clear association has not been established ^{59} ^{71} ^{73} ^{74} ^{82} ^{88} ^{90}. In one small study of 14 women with uncontrolled seizures, medroxyprogesterone reduced their seizure frequency by 30% ^{14}. However, use of many medications for seizure control reduce the contraceptive efficacy of many contraceptives ^{14})

Diabetes mellitus    (high doses of progestins may alter carbohydrate metabolism by an unknown mechanism, producing a mild decrease in glucose tolerance in some patients. New-onset diabetes mellitus and exacerbation of preexisting diabetes mellitus have been reported in patients taking high or chronic doses of megestrol ^{67}. Progestin-only oral contraceptives do not usually affect carbohydrate metabolism, but may occasionally affect lipid metabolism ^{185} ^{189} ^{195} ^{199} ^{200} ^{249}. No clinical significance on fasting blood glucose is seen in nondiabetics receiving low doses of oral progestins for contraception ^{71} ^{72} ^{74} ^{82} ^{86} ^{90} ^{131} ^{177})

    (levonorgestrel's effects on carbohydrate metabolism appear to be minimal for nondiabetics but are considered inconclusive for prediabetics and diabetics ^{88})

    (parenteral medroxyprogesterone may decrease glucose tolerance for some patients by an undetermined mechanism; it has been used with caution for contraception in diabetics ^{131} ^{137})

Hepatic disease or dysfunction, history of    (metabolism of progestins, specifically androgenic progestins, may be impaired and contribute to the hepatic condition ^{71} ^{72} ^{73} ^{74} ^{83} ^{86} ^{88} ^{199} ^{200})

Hyperlipidemia    (some progestins, specifically androgenic progestins, might increase LDL and lower HDL levels and aggravate problems in controlling hyperlipidemia ^{88} ^{90} ^{130} ^{197} ^{200} ^{235})

Significant risk factors for low bone mineral content    (the overall effect on bone density for progestins has yet to be established and may depend on type of progestin, dose, and gender and age of patient. A retrospective cross-sectional study has reported that women using parenteral medroxyprogesterone for contraception had bone density measurements lower than the control group of premenopausal women but higher than the control group of postmenopausal women. Specifically, medroxyprogesterone may temporarily increase the loss of trabecular bone and additionally increase the risk of osteoporosis. The greatest bone loss is evident in the early years of use, is usually reversible, and possibly reflects other factors, such as hypoestrogenism, when progestin is used alone. A prospective study has reported that the use of oral medroxyprogesterone alone for treatment of menopausal symptoms showed a protective effect against loss of bone; other studies, particularly those in which a progestin was combined with estrogen, have also shown a protective effect ^{05} ^{06} ^{14} ^{71} ^{123} ^{163} ^{188} ^{210})

» Thromboembolic disorders, including cerebrovascular disease, pulmonary embolism, retinal thrombosis, history of or
Thrombophlebitis, history of    (the large doses of progestins used to treat breast and prostate cancer have been associated with a slight risk of thrombogenic conditions; mechanism is unclear and may be due to the underlying condition. Problems have also occurred with megestrol ^{67} ^{134}. Problems have not been associated with low doses used for contraception, including parenteral medroxyprogesterone, progestin-only oral contraceptives, or levonorgestrel subdermal implants for patients with a history of thromboembolic disorders or thrombophlebitis ^{66} ^{71} ^{72} ^{73} ^{74} ^{82} ^{86} ^{88} ^{105} ^{111} ^{123} ^{130} ^{132} ^{135})

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Breast examinations    (should be performed routinely, especially with prolonged progestin use ^{61})

Papanicolaou (Pap) test and
Physical examination    (as determined by physician, with special attention being given to abdomen, breast and pelvic organs ^{61}; pre- and post-inspection of site of insertion and removal of levonorgestrel subdermal implants with annual inspection of implantation site during use ^{71} ^{72} ^{73} ^{86} ^{194})

Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent

Amenorrhea (stopping of menstrual periods)^{59}^{71}^{73}^{74}^{81}^{82}^{86}^{88}^{130}^{146}^{148}^{246}

breakthrough menstrual bleeding or metromenorrhagia (medium to heavy uterine bleeding between regular monthly periods )^{59}^{66}^{67}^{68}^{71}^{73}^{74}^{81}^{82}^{86}^{88}^{100}^{113}^{146}

hyperglycemia (dry mouth; frequent urination; loss of appetit; unusual thirst)—16% with high doses of megestrol^{115}

menorrhagia (increased amount of menstrual bleeding occurring at regular monthly periods)^{71}^{82}^{88}^{90}

spotting (light uterine bleeding between regular monthly periods)—17% for levonorgestrel subdermal implants or oral progestins for contraception ^{59} ^{71} ^{74} ^{81} ^{82} ^{86} ^{88} ^{100} ^{146}

Note: For all progestins, if abnormal uterine bleeding is persistent (longer than 10 days at a time) or recurring (heavier than normal menses occurring longer than 10 months after beginning therapy or more often than monthly), malignancy should be considered as a cause of the bleeding. ^{61} ^{71} ^{72} ^{194}
For progestins used for cycle control or as part of ovarian hormone therapy: Breakthrough uterine bleeding is not as prevalent as it is with progestin-only contraceptives; therefore, any unexpected uterine bleeding that persists for 3 to 6 months should be investigated. ^{194} ^{246}
For oral progestins for contraception: Breakthrough menstrual bleeding or spotting is common. ^{90} ^{232}
For parenteral medroxyprogesterone: Amenorrhea increases with duration of use (12 months—55% and 24 months—68%). ^{71} ^{73} Breakthrough menstrual bleeding occurs in 90% of users. ^{232}
For levonorgestrel subdermal implants: After 1 year of use of levonorgestrel subdermal implants, total uterine blood loss decreases from baseline levels of 31 mL per month to 24 mL per month. ^{148} Amenorrhea occurs in 9.4 to 15% of users of the subdermal implants and breakthrough menstrual bleeding occurs in 28% of users, persisting throughout treatment. ^{232} ^{240}

Incidence less frequent

Galactorrhea ^{73}^{74}^{86}^{88}(unexpected or increased flow of breast milk )

mental depression ^{59}^{71}^{72}^{73}^{74}^{81}^{82}^{86}^{146}

skin rash ^{66} ^{68} ^{71} ^{73} ^{82} ^{86} ^{88}

Incidence rare

Adrenal suppression or insufficiency or hypotension ^{249} (dizziness; nausea or vomiting; unusual tiredness or weakness)—may occur during chronic megestrol treatment or on its withdrawal ^{67}

Cushing's syndrome (backache; filling or rounding out of the face; irritability; menstrual irregularities; mental depression; unusual decrease in sexual desire or ability in men; unusual tiredness or weakness)— may occur during chronic megestrol treatment ^{67}

thromboembolism or thrombus formation (headache or migraine ^{86} ^{88}; loss of or change in speech, coordination, or vision ^{71}; pain or numbness in chest, arm, or leg ^{73} ^{74}; shortness of breath, unexplained ^{67} ^{68} ^{71})— severe and sudden, with high doses of progestins for noncontraceptive uses ^{111} ^{112} ^{115} ^{149}

Note: It is not clear if the thromboembolism or thrombus formation associated with use of progestins in high doses is due to the treatment or to the underlying condition that is being treated, such as cancer ^{190} ^{196}. Thrombophlebitis, pulmonary embolism, and heart failure have occurred with use of megestrol; fatalities occurred in some cases ^{68}.

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent

Abdominal pain or cramping ^{71}^{86}^{88}^{146}

diarrhea — 5% for oral levonorgestrel for postcoital contraception

dizziness

drowsiness ^{249}—for progesterone only

edema ^{68}(bloating or swelling of ankles or feet)

fatigue —17% for oral levonorgestrel for postcoital contraception

headache, mild —up to 24% with levonorgestrel subdermal implants^{67}^{68}^{71}^{73}^{74}^{81}^{86}^{88}^{146}^{148}

mood changes —up to 16% for levonorgestrel subdermal implants^{146}^{201}

nausea —23% for oral levonorgestrel for postcoital contraception

nervousness ^{71}^{73}^{74}^{81}^{86}^{88}

ovarian enlargement or ovarian cyst formation (abdominal pain)—10% for levonorgestrel subdermal implants^{148}^{177}

pain, redness, or skin irritation at the site of injection or implantation — including local skin color change and residual lump^{73}^{88}

unusual tiredness or weakness ^{66}^{71}^{73}^{74}^{81}

unusual or rapid weight gain ^{59} ^{67} ^{68} ^{71} ^{73} ^{74} ^{81} ^{82} ^{86} ^{88} ^{100} ^{139} ^{140}

vomiting —5% for oral levonorgestrel for postcoital contraception^{254}

Note: For parenteral medroxyprogesterone for contraception: Average weight gain is 2.5 to 7.5 kilograms (kg) after 1 to 6 years of use. ^{71}
Ovarian enlargement or ovarian cyst formation occurring with levonorgestrel subdermal implants is almost always transient and rarely requires surgery. ^{148} ^{177} ^{239}
For oral levonorgestrel for postcoital contraception: If vomiting occurs within one hour of taking a dose of levonorgestrel, the dose may have to be repeated^{254}.

Incidence less frequent

Acne ^{71}^{73}^{74}^{86}^{88}^{146}^{148}

breast pain or tenderness ^{67}^{73}^{74}^{86}^{88}

hot flashes ^{71}^{73}^{74}^{146}^{148}

insomnia (trouble in sleeping)^{71}^{73}^{74}

libido decrease (loss of sexual desire )^{66}^{71}^{81}^{86}

loss or gain of body, facial, or scalp hair ^{67}^{68}^{71}^{73}^{74}^{86}^{88}^{146}

melasma (brown spots on exposed skin, which may persist after treatment stops)^{59}^{73}^{81}^{82}^{86}

nausea —subsides in 3 months for low dose progestins for contraception ^{66} ^{68} ^{71} ^{73} ^{74} ^{81} ^{86} ^{88} ^{90} ^{100}

Those indicating need for medical attention if they occur after medication is discontinued

Adrenal suppression or insufficiency or hypotension ^{249} (dizziness; nausea or vomiting; unusual tiredness or weakness)—may occur on withdrawal of chronic megestrol treatment

delayed return of fertility in females (stopping of menstrual periods; unusual menstrual bleeding, continuing)

Note: Progestin-only oral contraceptives and progestins used for ovarian hormone therapy have not been shown to cause adrenal suppression or insufficiency or delayed return of fertility ^{249}.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Progestins—For Noncontraceptive Use (Systemic) or Progestins—For Contraceptive Use (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergy to peanuts, for oral or parenteral progesterone, or history of hypersensitivity to progestins

Carcinogenicity—
Studies are ongoing and have not been done with all progestins. Use of progestins with estrogens in ovarian hormone therapy lowers the incidences of endometrial hyperplasia and endometrial cancer. Significantly, a prolonged (8-year) study in women using injectable medroxyprogesterone for contraception has found a protective effect against endometrial cancer. Long-term studies of parenteral medroxyprogesterone have found no increase in overall risk of breast, ovarian, liver, or cervical cancer. Women 35 years of age or younger may have an increased risk of breast cancer during the first four years following initial use

Pregnancy—With the exception of hydroxyprogesterone and progesterone, use is not recommended during pregnancy. When progestins are used in doses for contraception, ectopic pregnancy is possible, although rare. Alternative methods of contraception should be used by fertile and sexually active females when high dose progestins are used for noncontraceptive purposes, such as in treatment of cancer; physician should be told immediately if pregnancy is suspected

Breast-feeding—Progestins are distributed into breast milk in variable amounts; high doses may increase or decrease the quantity or quality of breast milk while low doses have no effect on breast milk and are recommended for use in breast-feeding women needing contraception; adverse effects in the nursing infant have not been reported

Use in adolescents—
Adolescents tend to have a greater risk for sexually transmitted diseases (STDs) and have a higher failure rate for oral progestins for contraception because of compliance problems. Adolescents who are at increased risk for STDs or those failing to comply with strict dosing schedule for contraceptives (a strict 24-hour dose regimen for oral medications or replacement doses for contraceptive injection and implants) may be better served with another form of contraception

Dental—May predispose patient to increased bleeding and inflammation of the gingival tissues


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