Progesterone (Natural Micronized)

Progesterone (Natural Micronized) is a hormone agent belonging to the pharmacological class of progestins.

The FDA approved Progesterone (Natural Micronized) for the treatment of endometrial hyperplasia, secondary amenorrhea, and abnormal uterine bleeding due to hormonal imbalance.

When micronized soft-gelatin capsules are taken, progesterone levels in the blood reach their maximum in three hours. 96–99% of the binding is done by serum proteins, mainly transcortin and serum albumin. Pregnanediols and pregnanolones are produced by liver metabolism and are then conjugated for excretion in urine and bile, where they may be recycled or expelled in stools.

The most common side effects of Progesterone (Natural Micronized) include vaginal bleeding, vaginal discharge, and itching.

Progesterone (Natural Micronized) is available in capsules.

The molecule is available in the United States, Canada, the United Kingdom, Australia, Germany, France, Italy, Japan, India, Brazil and Mexico.

Progesterone (Natural Micronized) is a natural hormone agent belonging to the pharmacological class of progestins.

Progesterone soft gel capsules, an oral micronized form chemically identical to ovarian progesterone, enhance oral bioavailability. Progesterone, like progestins, binds to progesterone and estrogen receptors in the female reproductive tract, mammary gland, hypothalamus, and pituitary. Once attached, it slows the release of gonadotropin-releasing hormone (GnRH), inhibiting the pre-ovulatory LH surge. In women with adequate estrogen, progesterone transforms the endometrium and is vital for decidual tissue development, enhancing endometrial receptivity for embryo implantation and maintaining pregnancy. It stimulates mammary alveolar tissue growth and relaxes uterine smooth muscle, exhibiting minimal estrogen androgenic activity.

The time required for Progesterone (Natural Micronized) to show its effect effects may occur within hours.

The duration for which Progesterone (Natural Micronized) remains effective in the body lasts for several hours to days.

The maximum plasma concentration (Cmax) of Progesterone (Natural Micronized) typically occurs within approximately 1 to 6 hours (Tmax) after administration.

Progesterone (Natural Micronized) is available as capsules.

Capsules: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, a single daily dose should be given at bedtime. It can be taken with or without food as directed.

• Hormone replacement therapy
• Female Infertility
• Endometrial hyperplasia
• Amenorrhoea

• Hormone replacement therapy: In hormone replacement therapy (HRT), progesterone (naturally micronized) actively helps to maintain hormonal balance. It reduces the risk of endometrial hyperplasia and works in conjunction with estrogen therapy. Progesterone preserves the lining of the uterus, providing defence against problems brought on by estrogen. By actively promoting a more balanced and encompassing hormonal environment, HRT lowers the possible hazards associated with untreated estrogen therapy.

• Female Infertility: Natural Micronized Progesterone effectively promotes female conception by keeping the lining of the uterus healthy and providing an environment that is favourable for implantation. It is essential for maintaining early pregnancy and encouraging embryo survival. Furthermore, progesterone actively regulates the menstrual cycle, treating conditions that could lead to infertility.
• Endometrial hyperplasia: In endometrial hyperplasia, progesterone (naturally micronized) is helpful because it causes a secretory endometrial change, which inhibits excessive proliferation. It facilitates and sustains a balanced endometrial lining by creating an environment favourable for implantation. This lowers the chance of hyperplastic alterations by promoting overall endometrial health and reducing the risk of abnormal cell development.
• Amenorrhoea: In cases of amenorrhea, progesterone (naturally micronized) effectively improves hormonal imbalances and brings monthly regularity back. It helps a healthy menstrual cycle by encouraging the removal of the uterine lining. Because of progesterone's active function, irregular menstruation is lessened when it occurs.

• Hormone Replacement Therapy (HRT) actively maintains hormonal balance, reducing the risk of endometrial hyperplasia and defending against estrogen-induced issues.
• For Female Infertility, it promotes conception, maintains uterine health, and regulates the menstrual cycle.
• In Endometrial Hyperplasia, it inhibits excessive proliferation, sustaining a balanced endometrial lining.
• In Amenorrhea, it improves hormonal imbalances, restoring monthly regularity.

Orally: Progesterone (Natural Micronized) tablets) is commonly administered orally, typically as soft-gelatin capsules. The capsules contain micronized progesterone, allowing for improved absorption. The precise dosage and directions for administration are determined by the particular medical condition being treated as well as the advice of the healthcare professional.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Capsules: 100mg, 200mg

Progesterone (Natural Micronized) is available in the form of capsules.

Dose Adjustment in Adult Patients:

Prevention of Endometrial Hyperplasia: Every 28-day cycle, take 200 mg PO qHS for 12 consecutive days.

Amenorrhea Secondary: 400 mg PO qHS x 10 days

Progesterone (Natural Micronized) doesn’t usually require dietary changes. It is advised to maintain a balanced diet that is rich in fruits, whole grains, vegetables, lean proteins, and healthy fats is crucial. Reduce consumption of triggering agents like caffeine, alcohol, and spicy foods that induce hot flushes. Cease smoking to diminish hot flashes and lower the likelihood of stroke, heart disease, and cancer. Adherence to these dietary modifications and lifestyle changes supports overall well-being during Progesterone (Natural Micronized) use.

The dietary restriction should be individualized as per patient requirements.

Progesterone (Natural Micronized) may be contraindicated in the following conditions:-

• Known hypersensitivity to Progesterone or any of the excipients.
• Undiagnosed irregular vaginal bleeding.
• Past medical history of acute thrombophilia and thromboembolic illnesses
• Genital and breast cancer
• Unplanned pregnancy or ectopic pregnancy
• Diagnostic testing for pregnancy
• Apoplexy in the brain
• The existence of severe liver diseases or a history of severe liver diseases until the point at which the liver function results have stabilized.

Consider family history of breast cancer, DVT/PE, current/history of depression, endometriosis, Diabetes mellitus, Hypertension, bone mineral density changes, renal or hepatic impairment, bone metabolic disease, SLE, and conditions worsened by fluid retention (e.g., migraine, asthma, epilepsy).

Discontinue if jaundice, visual problems (may cause contact lens intolerance), signs of VTE, severe migraine, significant blood pressure increase, severe depression, or increased thromboembolic risk post-surgery develop.

Cease four weeks before major surgery or prolonged immobilization. Adjust warfarin or oral anticoagulant doses if needed. Evaluate OCP use concerning breast cancer risk, with varying study outcomes.

Assess individual risk factors for breast cancer, including early menstruation, late menopause, childbirth after 30, and nulliparity.

Examine any potential increased risk of cervical and liver cancer with OCP use; duration may influence risk. Caution with dizziness—use care when driving or operating machinery.

Postmenopausal women >65 may face an elevated risk of developing probable dementia. Exercise caution in patients with a history of depression.

Use carefully in conditions exacerbated by fluid retention, such as epilepsy, migraine, renal dysfunction, diabetes, or asthma.

In cases of partial or complete vision loss, diplopia, or sudden onset of proptosis, discontinue permanently if papilledema or retinal vascular lesions are observed upon examination.

It is unsafe to consume alcohol.

Caution when used during breastfeeding.

It can be safe to use during pregnancy.

Maintain a balanced diet; limit triggers like caffeine, alcohol, and spicy foods. Quit smoking.

The adverse reactions related to Progesterone (Natural Micronized) can be categorized as

• Common Adverse Effects: Headaches, breast tenderness, dizziness, abdominal pain, depression, breast pain, and viral disease.
• Less Common Adverse Effects: Fatigue, nausea, mood swings
• Rare Adverse Effects: Hypersensitivity reactions leading to severe skin rashes and unusual weight changes.

The clinically relevant drug interactions of Progesterone (Natural Micronized) are briefly summarized here.

Warfarin and Anticoagulants: Progesterone may intensify the effects of anticoagulants such as warfarin, which could raise the risk of bleeding. Anticoagulant dosage adjustments and routine monitoring may be required.

Rifampin: Rifampin is an antibiotic that may cause progesterone metabolism, which could reduce progesterone's effectiveness. When these drugs are taken together, progesterone levels may need to be monitored, and dosage modifications may be necessary.

Corticosteroids: Using corticosteroids concurrently may enhance their effects and raise the chance of fluid retention. It is advisable to exercise caution and monitor patients susceptible to fluid retention.

Insulin and Anti-Diabetic Drugs: Progesterone may impact insulin sensitivity by influencing glucose metabolism. It may be necessary to closely monitor blood glucose levels and modify insulin or antidiabetic drugs.

Barbiturates and Antiepileptic Drugs: Progesterone's efficacy may be diminished by barbiturates and certain antiepileptic drugs since they increase the hormone's metabolism. When taken together, progesterone dosage adjustments can be required.

The common side effects of Progesterone (Natural Micronized) include: -

Vaginal discharge

Joint pain

Headache

Abdominal pain

Vaginal haemorrhage

Pruritus (severe itching of the skin)

Nausea

Hot flushes

Weight Gain

Dizziness

Breast Tenderness

• Pregnancy

Pregnancy Category B (FDA): Could be acceptable. Either no danger has been shown by animal research, but human studies have yet to be conducted, or some risk has been shown by animal studies but not by human studies.

Data

Research on reproduction has been done on mice at doses up to nine times that of humans or rats at doses up to forty-four times that of humans or rabbits at a dose of ten micrograms per day administered locally within the uterus by an implanted device, on guinea pigs at doses roughly half that of humans or in rhesus monkeys at doses roughly that of humans, all based on body surface area. These studies have shown little to no evidence of decreased fertility or harm to the fetus as a result of progesterone.

Fertility

The impact of Progesterone (Natural Micronized) on fertility needs to be well-documented.

• Nursing Mothers

Nursing women on progestin have been found to have detectable progestin levels in their milk.

Caution should be used when giving progesterone (naturally micronized) to a breastfeeding woman.

• Pediatric Use

As per the FDA, Progesterone (Natural Micronized) in pediatric patients is not recommended.

Dose Adjustment in Kidney Impairment Patients:

There is no sufficient scientific evidence regarding the use and safety of Progesterone (Natural Micronized) in kidney impairment patients. There are no specific dosage adjustments provided.

Dose Adjustment in Hepatic Impairment Patients:

There are no specific dosage adjustments provided.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Progesterone (Natural Micronized).

Signs and Symptoms

Overconsumption of Progesterone (Natural Micronized) could lead to nausea, vomiting, and abdominal discomfort.

Management

There is no specific antidote or treatment for Progesterone (naturally micronised) overdosage, so treatment typically involves symptomatic and supportive measures. If ingestion is recent, gastric lavage or activated charcoal might limit absorption.

Nausea, vomiting, and abdominal discomfort can be managed symptomatically. If severe symptoms persist or worsen, or in case of significant ingestion, seeking immediate medical attention is recommended. Close vital sign monitoring is crucial, emphasizing timely medical intervention to mitigate potential risks from Progesterone (Natural Micronized) overdose.

Timely intervention and appropriate medical care are essential for ensuring the best possible outcome in cases of Progesterone (Natural Micronized) overdosage.

Pharmacodynamics:

By attaching to progesterone receptors in different organs and affecting gene expression, progesterone (Natural Micronized) carries out its pharmacodynamic actions. It creates an environment in the endometrium that is favourable to implantation. It also stops gonadotropins from being secreted, which prevents ovulation. It preserves the glandular structure of the breast. Additionally, the hormone affects cervical mucous, decreasing its receptiveness to sperm. Together, these activities assist the reproductive system, menstrual cycle management, and hormone replacement therapy for postmenopausal women.

Pharmacokinetics:

Absorption

Within three hours of oral progesterone treatment using micronized soft-gelatin capsules, maximal blood concentrations were reached.

Distribution

Ninety-six to ninety-nine per cent of progesterone is linked to serum proteins, mainly to transcortin (43–48 per cent) and serum albumin (50–54 per cent).

Metabolism

Pregnanediols and pregnanolones are the main byproducts of the liver's primary progesterone metabolism. In the liver, pregnanolones and pregnanediols are conjugated to glucuronide and sulfate metabolites.

Expelled in the bile, progesterone metabolites can undergo deconjugation and subsequent metabolism in the colon through reduction, dehydroxylation, and epimerization.

Elimination

Urine and bile contain the conjugates of pregnanediol and pregnanolone, glucuronide and sulfate, respectively. The kidneys are primarily responsible for excreting progesterone metabolites. Expelled progesterone metabolites from the bile may be recycled by the liver or eliminated in the stools.

• Malik S, Krishnaprasad K. Natural Micronized Progesterone Sustained Release (SR) and Luteal Phase: Role Redefined!! J Clin Diagn Res. 2016 Feb;10(2):QE01-4. doi: 10.7860/JCDR/2016/17278.7212. Epub 2016 Feb 1. PMID: 27042538; PMCID: PMC4800604.

• Wagh GN, Kundavi Shankar KM, Bachani S. A review of conventional and sustained-release formulations of oral natural micronized progesterone in obstetric indications. Drugs Context. 2021 Oct 13;10:2021-7-1. doi: 10.7573/dic.2021-7-1. PMID: 34721615; PMCID: PMC8527984.

• Majhi P, Bagga R, Kalra J, Sharma M. Intravaginal use of natural micronised progesterone to prevent pre-term birth: a randomised trial in India. J Obstet Gynaecol. 2009 Aug;29(6):493-8. doi: 10.1080/01443610902980878. PMID: 19697195. Hipolito Rodrigues MA, Gompel A. Micronized progesterone, progestins, and menopause hormone therapy. Women Health. 2021 Jan;61(1):3-14. doi: 10.1080/03630242.2020.1824956. Epub 2020 Sep 21. PMID: 32957843.

• Benifla JL, Dumont M, Levardon M, Foucher E, Cadiot G, Crenn-Hebert C, Heid M, Lelaidier C, Rosenbaum A, Bernuau J, Erlinger S, Frydman R, Madelenat P. Effets de la progestérone naturelle micronisée sur le foie au cours du troisième trimestre de la grossesse [Effects of micronized natural progesterone on the liver during the third trimester of pregnancy]. Contracept Fertil Sex. 1997 Feb;25(2):165-9. French. PMID: 9116778.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/019781s017,020843s011lbl.pdf
• https://www.nps.org.au/assets/medicines/99831e39-5b9a-4c68-b320-a66600f8ab0c.pdf
• US Food and Drug Administration (FDA) [Internet]. Maryland. USA; Package leaflet information for the user; Prometrium (progesterone)
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800604/