# Hormonal oral contraceptives

Hormonal oral contraceptives are preventive medications taken orally to avoid pregnancy in sexually active active females by manipulating their sex hormones. The first oral contraceptive was approved by the FDA and sold to the market in 1960. There are two types of hormonal oral contraceptives, namely Combined Oral Contraceptives and Progesterone Only Pills. Oral contraceptives, be it combined or progesterone-only, can effectively prevent pregnancy by regulating hormonal changes in the menstrual cycle, inhibiting ovulation, and altering cervical mucus to impede sperm mobility; combined pills have extra effects in menstrual cycle regulation and menstrual pain relief. Common off-label uses include menstrual suppression and acne relief, with Combined Oral Contraceptives having additional benefits in relieving menstrual migraine.

## The Menstrual Cycle

Hormonal oral contraceptives (HOCs) interact with hormonal changes in the menstrual cycle in females to prevent ovulation, and hence achieve contraception. In a 28-day menstrual cycle, there are the proliferative phase, ovulation, and then the secretory phase.
Menstruation marks the beginning of proliferative phase in day 1-14. In this period, the pituitary gland located near the brain secretes follicle-stimulating hormone (FSH) into the bloodstream to signal the development of follicle in ovary in the female reproductive system. While follicle serves as the chamber of ovum development, it secretes Oestrogen, a hormone that not only triggers the thickening of uterine lining in preparation for implantation, but also inhibits the secretion of FSH in pituitary via a negative feedback mechanism.
Specifically in ovulation, transient positive feedback by Oestrogen on FSH and Luteinising Hormone (LH) secretion from pituitary is permitted so that the release of mature ovum from follicle is triggered.
In secretory phase on day 14-28, this follicle then transforms into corpus luteum and continues releasing Oestrogen with Progesterone into bloodstream. While Oestrogen and Progesterone primarily aid the maintenance of thickness in uterine lining, the negative feedback in pituitary allows them to inhibit FSH and LH secretion. In the absence of LH, corpus luteum degenerates and ultimately causes blood Oestrogen and Progesterone levels to decline. Without these thickness maintaining agents, uterine lining breaks down and hence the presentation of menstruation.

## Mode of Action

Progesterone and Oestrogen, either in combination or with Progesterone-only, are the active pharmaceutical ingredients found in a HOC formulation. These medications are orally administered for systemic absorption to exert their effects. An artificially enhanced level of Progesterone throughout the menstrual cycle inhibits the pituitary secretion of FSH and LH such that their actions in stimulating follicular development and ovulation are prevented. Similarly, a boosted Oestrogen level activates the negative feedback mechanism in reducing FSH secretion from pituitary and therefore prevents follicular development. In the absence of a developed follicle, ovulation cannot occur so that fertilisation is made impossible and contraception is achieved. In comparison, Progesterone is more efficacious than Oestrogen not only because of its additional action in impeding LH, but also its ability to modulate the cervical mucus into sperm-repellent.

## Variants

Progesterone only Pills (POPs) POPs utilise Progestin, the synthetic form of Progesterone, as the only active pharmaceutical ingredient in the formulation. In the US, drospirenone and norethindrone are the most commonly used compounds in formulations.
Combined Oral Contraceptives (COCs) COCs are commonly classified into generations, referring to their order of development in history. This discussion may also help identify some key features in a variety of products. According to EMA, the first generation of COCs, which made use of high concentration of Oestrogen only, were those invented in the 1960s. In the second generation of products, Progestogens were introduced into the formulation while the concentration of Oestrogen was reduced. Starting from the 1990s, the progression in the development of COCs has been directed towards varying the type of Progestogen incorporated. These products are referred as the third and fourth generation.
Oestrogen ingredients: estradiol, ethinylestradiol, estetrol.
1st generation Progestin: norethindrone acetate, ethynodiol diacetate, lynestrenol, norethynodrel.
2nd generation Progestin: levonorgestrel, dl-norgestrel.
3rd generation Progestin: norgestimate, gestodene, desogestrel.

## Dosage Regimen

This section demonstrates the overall rationalisation of dosing route and intervals of HOCs, please seek advice and follow instructions from healthcare professionals in administering specific HOCs. Considering the menstrual cycle as a 28-day cycle, HOCs are available in packages of 21, 28, or 91 tablets. These pills have typically undergone unit dose optimisation so that they follow the administration pattern of once daily, every day or almost every day on a regular basis. Since they are formulated into daily doses, it is recommended that the medication should be taken at the same time every day to maximise efficacy.
For 21-tablet packs, the general instruction is to take one tablet daily for 21 days, followed by a 7-day blank interval without taking HOCs before initiating another 21-tablet pack. For 28-tablet packs, the 1st tablet from a new pack should be taken on the next day when the 28th tablet from an old pack was finished. While the 7-day blank period does not apply to 28-tablet packs, they will likely include tablets in distinctive colours indicating that they have an alternate amount of active ingredients, otherwise inactive ingredient or folate supplement only. The instruction for 91-tablet pack follows that of 28-tablet packs with some colour-distinguishable tablets which contain different amounts of medicine or supplement.
To acquire immediate contraceptive effects, the initiation of HOC dosing is recommended within the 1st-5th day from menstruation in order to discard other means of contraception. Specific to Progesterone only pills, even if dosing is initiated within five days, backup contraception is suggested in the first 48 hours since the first pill. In the case of dosing initiated after the 5th day from menstruation, effects usually take place after seven days and other contraceptive methods should remain in place until then.

## Advantages and Disadvantages
### Risks

In terms of protection in sexual intercourse, a sole reliance on HOCs does not defend one from sexually transmitted infections such as HPV. Additionally, breakthrough bleeding and spotting are exceptionally prevalent in the early stage of using HOCs. Although most reported side effects including nausea, headache, or mood swings will disappear as the therapy progresses or upon switching formulation, elevated blood pressure or blood clots in patients with cardiovascular conditions are documented side effects that requires medical attention if not termination of HOCs. It is because COCs uses have been found to be related to an increased risk of ischemic stroke or myocardial infarction, especially in COCs with >50 μg Oestrogen. Besides, some ongoing studies giving evidence on the association between HOC use and escalated breast cancer risks cannot be neglected.

### Benefits

The distinctive feature of HOCs when compared to other contraceptive methods is that they are less invasive and do not interfere with sex. Conclusive data suggest that the failure rate of contraception in using HOCs for the first year is 9% in typical use which allows missed doses, and <1% in perfect use. The efficacy of HOCs in preventing pregnancy is high overall. Furthermore, the regular use of HOC tends to not only ease premenstrual syndrome, but also allow lighter and less painful menstruation. In addition, the association between a suppressed risk of developing ovarian cancer and HOC use is proven.

## Accessibility

The availability of pharmaceutical products to the public is determined by the local governing body. In the US, the responsible organisation is the FDA. According to a press announcement on July 13, 2023, a daily hormonal oral contraceptive was first made accessible to the public without a prescription. Although this drug class was approved for prescription use as early as in 1973, it took an additional 50 years to de-escalate its legal status. Such allowance is made plausible thanks to the demonstration of its safe and effective use by the general public, not needing any guidance from healthcare professionals. Ultimately, the governing body should act accordingly to applicants' evidence and update the local legislation.

## Common off-label use
### Menstrual Suppression

Menstrual bleeding is not necessary in women who do not wish to conceive, therefore menstrual suppression may be implemented in women who do not want to have menstrual bleeding for convenience, gynecologic disorders, bleeding disorders or other medical conditions.
In the two types of HOCs, only COCs can achieve amenorrhea, while POPs can only reduce the amount of blood. The method of using COCs for menstrual suppression is to skip the 7 placebo pills and continue taking active pills after the 21 active pills. This can be used in extended method or continuous method. For extended method, patients who take active pills for 3, 4, or 6 months and then take placebo pills for a period of time will more likely experience withdrawal bleeding. The interval can be decided by the patients according to their own preferences. For continuous method, patients can take COCs for a year continuously without any placebo pills. In the first few months of extended or continuous use of COCs, unscheduled bleeding or spotting may occur. However, the bleeding or spotting is expected to resolve after a few months of use.
Menstrual suppression is commonly used for convenience especially when women go on vacation. It is also used for gynecologic disorders such as dysmenorrhea (commonly known as menstrual pain), symptoms related to premenstrual hormone change and excessive bleeding related to uterine fibroids. Patients can also benefit from menstrual suppression for bleeding disorders or chronic anemia.

### Menstrual migraine

Patients with menstrual Oestrogen-related migraine, but without aura and additional risk factors to stroke, can be benefited from COCs. However, older women and those with a strong family history of problematic headaches may find that using HOCs worsens their headache.

### Acne

Studies have shown that COCs are effective in reducing both inflammatory and non-inflammatory facial acne lesions. However, comparisons between different COCs have not been studied to understand if any brand is superior than the others. Oestrogen decreases sebum production by shrinking the sebaceous gland, increasing SHBG production to reduce unbound testosterone, and regulating LH and FSH levels. Currently, no studies have shown that POPs are effective against acne lesions.

## Precautions and Contraindications

According to WHO Medical Eligibility Criteria for Contraceptive Use 2015, Category 3 implies that the use of such contraception is usually not recommended, unless other more appropriate methods are neither available nor acceptable and with good resources of clinical judgment; Category 4 implies that the contraceptive method should not be used even with good resources of clinical judgment. Both categories suggest that the contraceptive method should not be used with limited resources for clinical judgment. The tables below summarise conditions of category 3 and 4 from WHO Medical Eligibility Criteria for Contraceptive Use 2015.

### Precautions and Contraindications for COCs

| Condition | Category |
| Breastfeeding ||
| for < 6 weeks postpartum | 4 |
| for ≥ 6 weeks to < 6 months postpartum | 3 |
| Postpartum (non-breastfeeding) ||
| < 21 days postpartum without other risk factors for VTE | 3 |
| < 21 days postpartum with other risk factors for VTE | 4 |
| ≥ 21 days to 42 days postpartum with other risk factors for VTE | 3 |
| Smoking ||
| age ≥ 35 years and smoking < 15 cigarettes/day | 3 |
| age ≥ 35 years and smoking ≥ 15 cigarettes/day | 4 |
| Multiple risk factors for arterial cardiovascular disease | 3/4* |
| Hypertension ||
| history of hypertension, where blood pressure CANNOT be evaluated | 3 |
| adequately controlled hypertension, where blood pressure CAN be evaluated | 3 |
| elevated blood pressure levels (properly taken measurements) with systolic 140–159 or diastolic 90–99 mm Hg | 3 |
| elevated blood pressure levels (properly taken measurements) with systolic ≥ 160 or diastolic ≥ 100 mm Hg | 4 |
| elevated blood pressure levels (properly taken measurements) with Vascular disease | 4 |
| Deep vein thrombosis (DVT) / Pulmonary embolism (PE) ||
| with History of DVT/PE | 4 |
| with acute DVT/PE | 4 |
| with DVT/PE and established on anticoagulant therapy | 4 |
| with Major surgery with prolonged immobilization | 4 |
| Known thrombogenic mutations | 4 |
| Current and history of ischemic heart disease | 4 |
| Stroke (history of cerebrovascular accident) | 4 |
| Complicated valvular heart disease | 4 |
| Positive (or unknown) antiphospholipid antibodies Systemic Lupus Erythematous | 4 |
| Headache ||
| migraine without aura of age ≥ 35 years (for initiation of COCs) | 3 |
| migraine without aura of age < 35 years (for continuation of COCs) | 3 |
| migraine without aura of age ≥ 35 years (for continuation of COCs) | 4 |
| migraine with aura, at any age (for initiation and continuation of COCs) | 4 |
| Breast cancer | |
| current Breast cancer | 4 |
| past Breast Cancer and no evidence of current disease for 5 years | 3 |
| Nephropathy/retinopathy/neuropathy | 3/4* |
| Other vascular disease or diabetes of > 20 years’ duration | 3/4* |
| Medically treated symptomatic gall bladder disease | 3 |
| Current symptomatic gall bladder disease | 3 |
| Past-COC related history of Cholestasis | 3 |
| Acute or flare viral hepatitis (for initiation of COCs) | 3/4* |
| Severe cirrhosis (decompensated) | 4 |
| Liver tumors ||
| hepatocellular adenoma | 4 |
| malignant (hepatoma) | 4 |
| On anticonvulsant therapy ||
| with phenytoin, carbamazepine, barbiturates, primidone, topiramate, oxcarbazepine | 3 |
| with Lamotrigine | 3 |
| On antimicrobial therapy with Rifampicin or rifabutin therapy | |
*The category should be assessed according to the severity of the condition.

### Precautions and Contraindications for POPs

| Condition | Category |
| Acute Deep vein thrombosis (DVT) / Pulmonary embolism (PE) | 3 |
| Current and history of ischemic heart disease (for continuation of POPs) | 3 |
| Stroke (history of cerebrovascular accident) (for continuation of POPs) | 3 |
| Positive (or unknown) antiphospholipid antibodies Systemic Lupus Erythematous | 3 |
| Migraine with aura, at any age (for continuation of POPs) | 3 |
| Breast Cancer ||
| current Breast Cancer | 4 |
| past Breast Cancer and no evidence of current disease for 5 years | 3 |
| Severe cirrhosis (decompensated) | 3 |
| Liver tumors ||
| hepatocellular adenoma | 3 |
| malignant (hepatoma) | 3 |
| On anticonvulsant therapy with phenytoin, carbamazepine, barbiturates, primidone, topiramate, oxcarbazepine | 3 |
| On antimicrobial therapy with Rifampicin or rifabutin therapy | 3 |
Different preparations contain varying amounts of hormones to address different physical conditions in women. Oral contraceptive pills should be started and used under medical supervision.