CRINONE 8% VAGINAL GEL

Indications

• Hormonal contraception
• Menstrual irregularities
• Endometrial hyperplasia
• Hormone replacement therapy
• Support of early pregnancy

Dosage

Children: Refer to the BNF for Children for any paediatric dosing recommendations concerning the use of progesterone.

Adults: Refer to the BNF for specific adult dosage guidelines, particularly for hormonal contraception and other indications.

Mechanism of action

Progesterone binds and activates its nuclear receptor, PR, which is significant in maintaining the endometrium during preparation for pregnancy. The progesterone receptor modulates gene expression that regulates the development and differentiation of reproductive tissues. It alters the consistency of cervical mucus, making it less favorable for sperm penetration and inhibits follicle-stimulating hormone (FSH) to prevent ovulation.

Pharmacodynamics

Progesterone acts primarily on the uterus by converting the proliferative phase to the secretory phase of the endometrium, preparing it for implantation. It increases the vascularity of the endometrium and stimulates mucous secretion while providing negative feedback to the anterior pituitary to decrease levels of FSH and LH. Thus, it prevents ovulation and promotes conditions conducive to pregnancy.

Pharmacokinetics

Progesterone is absorbed after administration and is metabolized primarily in the liver. The half-life of progesterone varies, with an average of about 5 minutes in circulation, but it can exert effects for longer due to its action on target tissues. It is excreted mainly in urine as conjugated metabolites. The pharmacokinetics can be influenced by factors such as route of administration, with intramuscular and oral forms demonstrating different absorption and bioavailability profiles.

Contra-indications

• Undiagnosed vaginal bleeding
• Active or severe hepatic disease
• History of breast cancer or known or suspected sex hormone-dependent tumors

Adverse effects

• Menstrual cycle irregularities
• Breast tenderness
• Dizziness
• Headache
• Nausea
• Skin reactions
• Weight change
• Abdominal distension
• Depressed mood
• Appetite change
• Fatigue
• Hypertension
• Libido disorder
• Nervousness
• Rash

Interactions

• Norethisterone
• Other hormonal contraceptives
• Antibiotics (may reduce effectiveness of progestogen-only contraceptives)

Precautions

• Caution in hepatic impairment
• Monitor for signs of thromboembolism
• Consider potential delayed return to fertility after discontinuation

Pregnancy

Progesterone is essential for maintaining pregnancy. Its use in non-contraceptive doses may cause masculinisation of female fetuses.

Breast-feeding

Progestogen-only contraceptives do not affect lactation. Higher doses may alter milk composition. Withhold breastfeeding for neonates with severe jaundice requiring treatment.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Norethisterone 5 mg tablets
• Norethisterone enantate 200 mg/1 ml solution for injection
• Noriday 350 microgram tablets
• Primolut N 5 mg tablets
• Utovlan 5 mg tablets

Mechanism of action

Progesterone binds and activates its nuclear receptor, _PR_, which plays an important part in the signaling of stimuli that maintain the endometrium during its preparation for pregnancy. Progesterone receptor (PR) is a member of the nuclear/steroid hormone receptor (SHR) family of ligand-dependent transcription factors that is expressed primarily in female reproductive tissue as well as the central nervous system. As a result of its binding its associated steroid hormone, progesterone, the progesterone receptor (PR) modulates the expression of genes that regulate the development, differentiation, and proliferation of target tissues. In humans, PR is found to be highly expressed in the stromal (connective tissue) cells during the secretory phase and during pregnancy. Progesterone may prevent pregnancy by changing the consistency of cervical mucus to be unfavorable for sperm penetration, and by inhibiting follicle-stimulating hormone (FSH), which normally causes ovulation. With perfect use, the first-year failure rate for progestin-only oral contraceptives is approximately 0.5%. The typical failure rate, however, is estimated to be approximately 5%, due to late or missed pills. Progesterone is a progestinic hormone secreted mainly from the corpus luteum of the ovary during the latter half of the menstrual cycle. Progesterone is formed from steroid precursors in the ovary, testis, adrenal cortex, and placenta. Luteinizing hormone (LH) stimulates the synthesis and secretion of progesterone from the corpus luteum. Progesterone is necessary for nidation (implantation) of the ovum and for maintenance of pregnancy. Although the hormone is secreted mainly during the luteal phase of the menstrual cycle, small amounts of progesterone are also secreted during the follicular phase. High concentrations of the hormone are secreted during the latter part of pregnancy. Amounts comparable to those secreted in women during the follicular phase have been shown to be secreted in males. Progesterone shares the pharmacologic actions of the progestins. In women with adequate endogenous estrogen, progesterone transforms a proliferative endometrium into a secretory one. The abrupt decline in the secretion of progesterone at the end of the menstrual cycle is principally responsible for the onset of menstruation. Progesterone also stimulates the growth of mammary alveolar tissue and relaxes uterine smooth muscle. Progesterone has minimal estrogenic and androgenic activity. Progesterone released during the luteal phase of the cycle decreases estrogen driven endometrial proliferation and leads to the development of a secretory endometrium ... . The abrupt decline in the release of progesterone from the corpus luteum at the end of the cycle is the main determinant of the onset of menstruation. If the duration of the luteal phase is artificially lengthened, either by sustaining luteal function or by treatment with progesterone, decidual changes in the endometrial stroma similar to those seen in early pregnancy can be induced. Under normal circumstances, estrogen antecedes and accompanies progesterone in its action upon the endometrium and is essential to the development of the normal menstrual pattern. Progesterone also increases the ventilatory response of the respiratory centers to carbon dioxide and leads to reduced arterial and alveolar PC02 in the luteal phase of the menstrual cycle and during pregnancy. Progesterone also may have depressant and hypnotic actions in the CNS, which may account for reports of drowsiness after hormone administration. For more Mechanism of Action (Complete) data for PROGESTERONE (12 total), please visit the HSDB record page.

Pharmacodynamics

Progesterone, depending on concentration and dosage form, and timing of exposure may have several pharmacodynamic effects. These actions, according, to various preparations, are listed below: General effects Progesterone is the main hormone of the corpus luteum and the placenta. It acts on the uterus by changing the proliferative phase to the secretory phase of the endometrium (inner mucous lining of the uterus). This hormone, stimulated by a hormone called _luteinizing hormone_ (LH) is the main hormone during the secretory phase to prepare the corpus luteum and the endometrium for implantation of a fertilized ovum. As the luteal phase concludes, the progesterone hormone sends negative feedback to the anterior pituitary gland in the brain to decrease FSH (follicle stimulating hormone) and LH (luteinizing hormone) levels. This prevents ovulation and maturation of oocytes (immature egg cells). The endometrium then prepares for pregnancy by increasing its vascularity (blood vessels) and stimulating mucous secretion. This process occurs by progesterone stimulating the endometrium to decrease endometrial proliferation, leading to a decreased uterine lining thickness, developing more complex uterine glands, collecting energy in the form of glycogen, and providing more uterine blood vessel surface area suitable for supporting a growing embryo. As opposed to cervical mucous changes observed during the proliferative phase and ovulation, progesterone decreases and thickens the cervical mucus, rendering it less elastic. This change occurs because the fertilization time period has passed, and a specific consistency of mucous amenable to sperm entry is no longer required. **Gelatinized capsules** Progesterone capsules are an oral dosage form of micronized progesterone which, chemically identical to progesterone of ovarian origin. Progesterone capsules have all the properties of endogenous progesterone with induction of a secretory phase endometrium with gestagenic, antiestrogenic, slightly antiandrogenic and anti-aldosterone effects. Progesterone opposes the effects of estrogen on the uterus, and is beneficial in women with unopposed estrogen exposure, which carries an increased risk of malignancy. **Vaginal gel and vaginal insert** The gel preparation mimics the effects of naturally occurring progesterone. In the presence of adequate levels of estrogen, progesterone converts a proliferative endometrium into secretory endometrium. This means that the endometrium changes from a growing and thickening stage into a subsequent preparation stage for pregnancy, which involves further preparatory changes. Progesterone is necessary for the development of decidual tissue (specialized tissue amenable to supporting a possible pregnancy). Progesterone is required to increase endometrial receptivity for the implantation of a fertilized embryo. Once an embryo is implanted, progesterone helps to maintain the pregnancy. **Injection (intramuscular)** Intramuscularly injected progesterone increases serum progesterone and aids in the prevention of endometrial tissue overgrowth due to unopposed estrogen (which leads to abnormal uterine bleeding and sometimes uterine cancer),. In the absence or deficiency of progesterone, the endometrium continually proliferates, eventually outgrowing its limited blood supply, shedding incompletely, and leading to abnormal and/or profuse bleeding as well as malignancy. **Tablets, contraceptive** Progesterone-only contraceptive tablets prevent conception by suppressing ovulation in about half of users, causing a thickening of cervical mucus to inhibit sperm movement, lowering the midcycle LH and FSH hormone peaks, slowing the movement of the ovum through the fallopian tubes, and causing secretory changes in the endometrium as described above.