ESTRACEPTIVE: Synergistic Scaffolds

31 August 2021

ESTRACEPTIVE: Synergistic Scaffolds

ESTRACEPTIVE (Norgestimate 250 mcg + Ethinyl Estradiol 35 mcg) as a monophasic contraceptive works by preventing ovulation. Through:

Inhibition of the midcycle surge of LH
Diminishing endogenous Progestine, so ovulation does not occur.
With minimal androgenic adverse effects among 3^rd Generation Progestines, and other off-target reactions.
Although Norgestimate 250 mcg (the progestin component) alone can exert these Effects alone, the combination with Ethynyl Estradiol 35 mcg synergistically decreases plasma gonadotropin levels and suppresses ovulation more consistently.
Estraceptive actions of estrogens and progestins on the hypothalamic-pituitary-ovarian axis during the menstrual cycle, several effects contribute to the blockade of ovulation.
Progesterone diminishes the frequency of GnRH pulses. Because the proper frequency of LH pulses is essential for ovulation.
Decrease pituitary responsiveness to GnRH.
Suppress FSH release from the pituitary during the follicular phase of the menstrual cycle, so diminish follicular development.
After discontinuing current low-dose formulations, return to ovulation is usually rapid. However, because the suppression is so quickly reversible, there is less room for error when using the current low dose with a short biological half-life <24 hours.
Women should be advised that the most important pills to remember to take are the first 7 ones of each cycle.
Other effects may contribute to a minor extent to the extraordinary efficacy of Estraceptive
Making Cervical mucus viscid, thick, and scanty, thus preventing sperm penetration and inhibiting capacitation of the sperm.
Decreasing motility of the uterus and oviduct thus inhibiting ova and sperm transport.
Diminishing endometrial glandular production of glycogen, making less energy available for the blastocyst to survive in the uterine cavity. Decreasing ovarian responsiveness to gonadotropin stimulation.

Synergistic Scaffolds of Estraceptive

Norgestimate 250 mcg

ESTRACEPTIVE is Composed of synthetic estrogen plus progestin. The progestin component provides most of the contraceptive protection while the estrogen provides cycle control and boosts the contraceptive effectiveness of the progestin.
Selective, gonane-type progestins with potent negative-feedback action on the hypothalamic-pituitary-gonadal axis and a high affinity for progesterone receptors.’
19-nortestosterone derivatives with structural changes that result in maintained menstrual cycle control while reducing androgenic adverse effects.
Has a C-17 acetate group as well as a unique C-3 oxime group, which minimizes its androgenicity by inhibiting its ability to bind to androgen receptors.

Progesterone and derivatives originate in the corpus luteum of the human ovary. have several features and mechanisms of action:

Making endometrium not receptive to ovum implantation
Thickening of cervical mucus
Inhibit spontaneous uterine contraction.’
Some with anti-androgenic properties making them highly potent
Has no carcinogenicity nor marked undesired cardiovascular side effects or adverse effects on the breast and other reproductive organs.

Development of Progestines:

1st Gen. Norethynodrel NEL – Norethisterone NETA
2nd Gen. Levonorgestrel LNG
3rd Gen. Gestodene GEST– Desogestrel DES- Norgestimate NGM
4th Gen. Drospirenone DROSP – Dienogest DNG only Germany

Estrogens

Mechanism of action is mediated by:

Provides a good cycle control
Prevent estrogen deficiency symptoms due to low secretion of endogenous estrogens as a consequence of inhibition of follicular growth.

Estrogen based formulations

High EE dose: 50 mcg, older combinations
Low EE dose: 30-35 mcg
Ultra-low dose: 20 mcg

Ethinyl-estradiol (EE) 35mcg

Is a potent orally active estrogen the hormonal potency of EE is determined by the bioavailable (‘free’) fraction of the circulating steroid, the intracellular production, and inactivation rate?
A greater cycle control may be achieved by lowering the EE (to be <50mcg as all old oral contraceptives) component of an OC in a balanced ratio with the same progestin, but the absolute quantity of EE in a given pill may be less important than maintaining a balance between the 2 hormones or less important than the impact of different progestins on breakthrough bleeding rates.
The anti-estrogenic effect of progestins is based mainly on the suppression of estrogen receptors and activation of enzymes involved in estrogen metabolism, as well as on the differentiation of the functional layer of the endometrium.

Factors contributing to breakthrough bleeding (bleeding in the middle of cycles):

Physiological effects of OCs on the endometrium
OC-related parameters, including dose, formulation.
Women’s behavior, including compliance.
Using concomitant medications.
Smoking, and benign or malignant pathology.

Estraceptive has a low EE dose of 35 mcg

Why?

Using the optimum dose to help Norgestimate to suppress ovulation and overcome the anti-estrogenic medium produced like bleeding irregularities. A higher dose would cost us serious estrogenic and metabolic problems like cardiovascular and blood glucose issues.

Estrogen/Progesterone balance (Norgestimate 250 mcg + Ethinyl Estradiol 35 mcg)

. So, the target dose of progestin is to produce secretory changes in the estrogen-primed endometrium.
Estraceptive shows complementary actions of estrogens and Norgestimate in the levels of androgenic and estrogenic activities and the hypothalamic-pituitary levels.
Older Progestines fully suppressed fertility but inhibited ovulation about 70% of the time and EE inhibited progestin-induced bleeding irregularity but was not fully effective alone in blocking ovulation. Together, the two agents provided total anti-ovulatory activity.
Thus, there is a Synergy in ESTRACEPTIVEÒ actions. As higher doses of NGM can create a degree of hypothalamic-pituitary suppression that exceeds the therapeutic need for ovulation inhibition (200 mcg). with estrogen in doses sufficient to control irregular cyclic bleeding but not high to cause serious metabolic hazards.

Estraceptive Scaffolds

ESTRACEPTIVE

Norgestimate and Norelgestromin, the major serum metabolite, combine high progestational activity with minimal intrinsic androgenicity

As it doesn’t counteract the estrogen-induced increases in sex hormone-binding globulin (SHBG), resulting in lower serum testosterone yielding better estrogen-progestin synergism. With recent interesting evidence concerning its direct inhibitory effect on the pituitary and the hypothalamus.

Pharmacokinetics

ESTRACEPTIVEÒ is rapidly absorbed following oral administration. Norgestimate is rapidly and completely metabolized by first-pass (intestinal and/or hepatic) mechanisms to its major active metabolites.

Norelgestromin (NGMN)
Levonorgestrel (LNG) (40–70 µg)

Peak serum concentrations of NGMN and EE are generally reached by 2 hours after administration of ESTRACEPTIVEÒ.

NGMN is following NGM 250 mcg. The steady-state concentration of EE is achieved by Day 7 of each dosing cycle. Steady-state concentrations of NGMN and NG are achieved by Day 21.

Metabolism

Norelgestromin and Norgestrel are highly bound (>97%) to serum proteins. Norelgestromin is bound to albumin and not to SHBG, while Norgestrel is bound primarily to SHBG.

Ethinyl estradiol is extensively bound (>97%) to serum albumin and induces an increase in the serum concentrations of SHBG.

Bioavailability

With being a prodrug, Norgestimate act in a balanced bioavailability model vs Desogestrel and Gestodene
Its molecule was designed to minimize its androgenicity while beginning the ovulation inhibitory actions with moderate PR affinity.
Then Norgestimate proceeds through its metabolites Norelgestromin and Norgestrel, with their super PR affinity in a reliable plasma concentration and period of time.

The Annals of Pharmacotherapy • 1995 July/August, Volume 29 • 737

Norelgestromin, Levonorgestrel are not bound to SHBG nor to CBG (corticosteroid binding globulin). The inactivation takes place through reduction and hydroxylation reactions, resulting in the formation of LNG metabolites.

Progesterone Receptor affinity

Norgestimate is a progestin, an agonist of the progesterone receptor. The relative binding affinities of Norgestimate and its active metabolites for the progesterone receptor compared to Progesterone (100%) are:
15% for Norgestimate
10% for Norelgestromin
150% for levonorgestrel
135% for levonorgestrel acetate.
Because of their low concentrations, Norgestimate and levonorgestrel acetate are not thought to contribute significantly to the biological activity of Norgestimate.
In addition, although levonorgestrel binds to the progesterone receptor with a much higher affinity than Norelgestromin, levonorgestrel has a high affinity for sex hormone-binding globulin (SHBG) (87% of that of testosterone), which may limit its activity, whereas Norelgestromin does not bind to SHBG. The ovulation-inhibiting dosage of Norgestimate is 20mcg/day.

Sex-Hormone Binding Globulin

As Testosterone, and estradiol circulate in the bloodstream, loosely bound mostly to serum albumin (~54%), and a lesser extent bound tightly to SHBG (~44%). Only a very small fraction of about 1 to 2% is unbound, or “free,” and thus biologically active and able to enter a cell and activate its receptor. Less than 1% of progesterone (natural progestin) is bound to SHBG.
SHBG inhibits the function of these hormones. Thus, the bioavailability of sex hormones and progestins is influenced by the level of SHBG.
SHBG levels are usually about twice as high in women as in men. In women, SHBG serves to limit exposure to both androgens and estrogens, avoiding major health hazards as hyperandrogenism and endometrial cancer respectively.
During pregnancy, due to activation of SHBG production in the liver by high estrogen levels, SHBG levels increase by five-fold to ten-fold. The high SHBG levels during pregnancy may serve to protect the mother from exposure to fetal androgens that escape metabolism by the placenta.

Androgenic and Anti-androgenic Activity

Progestins chemically resemble testosterone (19-nortestosterone derivatives) with structural changes that result in maintained menstrual cycle control while reducing androgenic adverse effects. And yet still have an inherent degree of androgenic activity. The more recently introduced progestins (Norgestimate (Estraceptive), Desogestrel (Marvelon), and Gestodene (Gynera)) are more selective and have less androgenic activity.
Such low-androgenic activity is meant to allow the effects of the estrogen component unlike the older progestins (2^nd Generation progestins). And are associated with higher sex hormone-binding globulin (SHBG) and other liver globulins compared with combination products with the same estrogen dose and a less selective progestin
Third-generation progestins, derived from the gonane Norgestrel, have high selectivity and demonstrate high progestational activity and low androgenic activity, and even anti-androgenic effects when compared with the other gonanes.
The degree of androgenicity in the progestin component of OCs influences changes in lipid and carbohydrate metabolism. Both abnormal lipid concentrations and uncontrolled glucose can contribute to the development of atherosclerosis. By removing or minimizing the androgenic effects, the risk of atherogenesis should be decreased.

Norgestimate (ESTRACEPTIVE®), is packed with Ethinyl group attached to enhance the oral activity of these agents because they are not as rapidly metabolized as they pass through the intestinal mucosa and the liver through the portal system. As well as a unique C-3 oxime group, which minimizes its androgenicity by inhibiting its ability to bind to androgen receptors.

Gestodene (Gynera) and (Desogestrel) Marvelon lack this unique feature and so possess a low androgenic effect as they bind Sex Hormone Binding Globulin (SHBG).

Drospirenone (Yasmin), a progestin structurally related to spironolactone. This progestin exhibits progestogenic, anti-mineralocorticoid, and anti-androgenic effects as well as a profound Glucocorticoid activity (27% of Dexamethasone) that may alter blood glucose, immunity profiles

Selectivity index

The ratio between the Androgen receptor affinity and Estrogen receptor affinity. Since all synthetic Progestines are testosterone derivatives, and testosterone is an estrogen precursor. Non-selective progestin (as Gestodene) is the one who has off-target tissue effect, binding to estrogen receptor and thus might cause less estrogen-related problems as VTE, CVD

Excretion

The metabolites of Norelgestromin and Ethinyl estradiol are eliminated by renal and fecal pathways.

Dosage

The dosage of ESRTRACEPTIVE® for the initial cycle of therapy is one tablet administered daily from the 1st day through the 21st day of the menstrual cycle, counting the first day of menstrual flow.
Missing cases
- If the patient misses one (1) tablet in Weeks 1, 2, or 3, the tablet should be taken as soon as she remembers.
- If the patient misses two (2) active tablets in Week 1 or Week 2, the patient should take two (2) tablets the day she remembers and two (2) tablets the next day; and then continue taking one (1) tablet a day until she finishes the pack.
- The patient should be instructed to use a backup method of birth control such as a condom if she has sex in the seven (7) days after missing pills.
- If the patient misses two (2) tablets in the third week or misses three (3) or more tablets in a row, the patient should throw out the rest of the pack and start a new pack that same day. The patient should be instructed to use a backup method of birth control if she has sex in the seven (7) days after missing pills.
ESTRACEPTIVE® for contraception may be initiated 4 weeks postpartum in women who elect not to breastfeed.
When the tablets are administered during the postpartum period, the increased risk of thromboembolic disease associated with the postpartum period must be considered the possibility of ovulation and conception before initiation of medication should be considered as well.

Contraceptive efficacy

Two indicators are used to judge contraception efficacy: first what are the pregnancy rates in perfect compliance and conditions (perfect use), and the other indicator is the pregnancy rates that happened in typical living conditions (Typical use). And to get such data, statistics scientists used two models to judge the success of a contraception method or pill.

Time table analysis. Calculation of a separate contraceptive effectiveness rate for each month of the study, as well as for a standard period of time (usually 12 months).
Pearl Index. “number of unintended pregnancies in 100 normally fertile women over the period of one year

The method failure rate for COC is low, but the failure rate due to patient negligence is higher and influenced i.e. by irregular intake, missing pills.
With perfect use, the pregnancy rate is 0.2–0.3% at the end of 1 year with all products. However, the typical use failure rate is higher and varies between 3 and 8% depending on the population and bioavailability of the progestin component of the pill.

3rd Generation COCs have a 99 percent effectiveness rate means that if 100 women used birth control pills for one year, one woman in the group would get pregnant

Parameters affecting contraceptive efficacy

A comprehensive analysis was done by Dinger et al. (2009) [155] as one part of the EURAS-OC-study in 112,659 women-years of exposure and 545 unplanned pregnancies showed that the potential reasons for contraceptive failure were associated with

Irregular OC intake in 230 (42.2%)
Vomiting and/or diarrhea in 100 (18.3%)
Use of antibiotics in 85 cases (15.6%).

Drug ability to exert Inhibition of ovulation

The combination estrogen-progestin formulations doses consistently inhibit the mid-cycle luteinizing hormone (LH) surge and effectively prevent ovulation

Type of progestin (as mentioned)

Age

Female fertility peaks between age 20 and 30 years.
A lower rate of contraceptive failure was found in women who were ≥ 30 years old and in women who had used OCs for a longer duration of time.

Duration of use:

As a result of being the most conscientious users and/or the least fertile users.

Parity

Parous (who got pregnant before) women were more likely to experience a pregnancy during OC use than nulliparous (who hasn’t got pregnant before) women, among any group of nulliparous women will be some women who are infertile (or have infertile partners)

Body mass

The EURAS-study shows little or no impact of body composition on contraceptive effectiveness of COC.

Estraceptive in practice guidelines- profiles

The goal of the health care provider

Is to match a user with a contraceptive method that will be used safely, correctly, and consistently. According to Age, motivation, sexual practices, financial ability, religious beliefs, reproductive history and plans, and overall health status of the user. User’s health and the presence of cardiovascular risk factors including smoking status may preclude some hormonal methods.

Patient/Consumer profiles

New-Start Healthy Patient (Adolescents).

Start with monophasic 35 mcg EE- Estraceptive to have better bleeding control and ultimately better compliance.
Going with the lowest dose of 20 mcg in adolescents may be associated with a lack of bleeding control, a leading cause of discontinuation.
Often used in young girls not at risk for pregnancy because of the many non-contraceptive benefits:
- Dysmenorrhea
- Bleeding control.
- Acne,
- Androgenic problems.

Early reproductive (18–29 years)

First choice: Estraceptive
Young women may have increased bleeding problems on 20mcg OCs
Use of a levonorgestrel or Norgestimate (more safe combination)-containing pill is associated with good bleeding control.
Dysmenorrhea, bleeding control: Using Estraceptive with its balanced EE/NG
PMS, PMDD, or fluid retention: using Estraceptive is safer than Drospirenone for its corticosteroid side effects.
Acne, androgenic problems: Consider low-androgenic progestin OCs Norgestimate

Late reproductive (30–35 years)

First choice: Estraceptive
- Menorrhagia (heavy menses): Switching to pill with a higher progestin to estrogen ratio results in less endometrial stimulation and may result in less menstrual bleeding.
- Bleeding problems: all OCs show benefit. If midcycle bleeding and spotting is a problem while on OC, consider switching to an OC with stronger progestin, such as one with levonorgestrel, or consider switching to a higher EE does OC. Estrogen increases endometrial growth and may improve bleeding control.
- Fibroids or endometriosis: all OCs may show benefit. Consider a stronger progestin OC, such as one with levonorgestrel, or OC with as low a dose of EE as possible.
- Significant menstrual-related problems: consider a low-dose monophasic OC
- Obesity: for heavier women (>70kg), consideration of EE35-mcg pill, Using more than EE35-mcg OCs may increase the risk of venous thromboembolism and a risk-benefit ratio should be considered. As a user gets older, the risk of thrombosis may increase and fecundity decreases, therefore, using a low EE does OC may be considered. IUDs, or tubal sterilization.

Perimenopausal or women over 35 years old. healthy, non-hypertensive, nonsmokers

The first choice is Estraceptive
The age group with longstanding obesity, hypertension, cigarette smoking, known or suspected vascular disease, or diabetes may consider progestin-only methods, barriers, IUDs, or tubal sterilization.
Perimenopausal symptoms (headaches, hot flushes) during the pill-free interval: consider switching to the low-risk Estraceptive with the better biological profile as DSG-containing OCs have an elevated risk of venous thromboembolism.

Clinical Evidence

ATE risk FSRH Faculty of Sexual and Reproductive Health – July 2019, evidence level 2+

Combined oral contraceptives (COCs) containing higher EE doses may be associated with a greater risk of arterial thrombotic events than lower EE doses.

DRSP had an increased risk of ATE compared to women using preparations of COC containing 20–35 μg EE and LNG, norethisterone, or Norgestimate

Effect of progestin type on VTE risk FSRH – evidence level 2+

A systematic review and recent meta-analyses

The use of low-dose COC (<50 μg EE) containing cyproterone acetate, desogestrel, gestodene, or DRSP was associated with a significant 5- to 2-fold risk of VTE compared to the use of COC containing LNG.
Norgestimate COC was found to be associated with similar VTE risk to LNG COC. These findings are consistent with those of other recent meta-analyses
In 2014, the EMA published estimated figures for absolute risk of VTE in users of CHC

Effect of dose of EE on VTE risk, FSRH July 2019 evidence level 2+

A systematic review and meta-analysis suggested that VTE risk among users of COC is related to the dose of EE

A Higher EE dose is associated with greater VTE risk. The meta-analysis concluded that a 50 μg EE/LNG COC was associated with RR (relative risk) for VTE of 1 (95% CI 1.4–3.2) and 2.3 (95% CI 1.3–4.2) compared with a 30 μg and 20 μg EE/LNG COC.

Unscheduled bleeding with Ultra-low EE dose, FSRH July 2019 evidence level 1+

A2013 Cochrane Review of 22 RCTs, Randomized Clinical Trials concluded that:

Women using 20 mcg of EE experienced higher rates of unscheduled bleeding than women using >20 mcg.
Even when the progestogen component was the same in both groups. Women taking 20 μg EE were more likely to report irregular bleeding (OR 1.56; 95% CI 1.10– 2.20). The difference between the incidences of unscheduled bleeding was statistically significant for 8 of the 12 months of follow-up.

ASRM, American Society for Reproductive Medicine Level II-2.VOL. 107 NO. 1 / JANUARY 2017

Studies have shown an increased risk of VTE with third-generation progestins except for norgestimate, which has been found to have a risk similar to levonorgestrel.

Cohort and case-control studies have also shown an increased VTE risk with the fourth-generation progestin Drospirenone. A recent large US cohort study of over 100,000 women who were new users of Drospirenone, compared with over 300,000 women who were new users of second-generation combined oral contraception noted an increased risk of VTE in the Drospirenone group

Low-risk, Expert Opin Drug Saf. 2014 Oct.

Hormonal contraception, thrombosis, and age

Combined hormonal contraceptives with desogestrel, gestodene, Drospirenone, or cyproterone acetate (high-risk products) confer a six-fold increased risk of venous thromboembolism as compared with non-users, and about twice the risk as compared with users of products with norethisterone, levonorgestrel, or Norgestimate (low-risk products).

Meta-Analysis-Acta Obstet Gynecol Scand Suppl1992

Selectivity and minimal androgenicity of Norgestimate in monophasic and triphasic oral contraceptives

The contraceptive progestin Norgestimate (NGM) has a high affinity for uterine progestin receptors and a lack of affinity for androgen receptors similar to that of natural progesterone
NGM’s selectivity results in excellent efficacy, cycle control, and minimal androgenicity when it is combined with Ethinyl estradiol (EE). Clinical studies of a monophasic regimen of NGM/EE indicate a positive impact on lipid metabolism, revealing an increase in serum levels of high-density lipoprotein cholesterol with a concomitant and significant decrease in the low-density lipoprotein/high-density lipoprotein cholesterol ratio.
Little impact on carbohydrate metabolism was noted. Serum levels of sex hormone-binding globulin, an indicator of androgen-estrogen balance, also increased significantly with NGM/EE following its low androgenic activity.

NGM’s lack of estrogenicity was evidenced by unchanged prolactin levels and absence of effect on the coagulation system.

Lipid profile, Int J Fertil Menopausal Stud. 1995;40 Suppl 2:98-104.

Metabolic profile of six oral contraceptives containing norgestimate, gestodene, and desogestrel

The only significant change, a slight decrease, in the LDL/HDL ratio occurred with the use of the Norgestimate

Thrombo-embolism, Eur J Contracept Reprod Health Care. 2012 Feb.

Venous and pulmonary thromboembolism and combined hormonal contraceptives. Systematic review and meta-analysis

25 studies meeting the inclusion in the meta-analysis. The pooled relative risks of VTE associated with the various CHCs, depending on their progestogen, were: gestodene vs. levonorgestrel 1.33 (95% confidence interval [CI]: 1.08-1.63); desogestrel vs. levonorgestrel 1.93 (95% CI: 1.31-2.83); and Drospirenone vs. levonorgestrel 1.67 (95% CI: 1.10-2.55).
The pooled adjusted odds ratio for norgestimate vs. levonorgestrel was 1.11 (95% CI: 0.84-1.46).
Conclusions: The safest CHCs in terms of VTE are those containing levonorgestrel or norgestimate.

Low-risk, Clin Obstet Gynecol. 1995 Dec. S L Corson

Norgestimate

Clinicians who believe in the potential for clinical consequences associated with changes in lipid and carbohydrate metabolism should make NGM their first choice OC progestin

Clinical impact, J Reprod Med. 2001 Jul.

Norgestimate. From the laboratory to three clinical indications

NGM is swiftly converted into its main metabolite, the 17-deacetylated norgestimate (norelgestromin), which carries the progestogenic properties of NGM. The metabolite reaches a mean peak concentration of 3,500 pg/mL 1.5 hours after intake and has a half-life of > 24 hours.
The progestogenic potency of NGM and its main metabolite is comparable to that of progesterone.
The doses of NGM in OCs effectively inhibit ovulation and control uterine bleeding.
NGM has a low androgenic impact and does not interfere with the positive metabolic actions of estrogens, notably the estrogen-induced increase in high-density lipoprotein levels.
OCs with NGM and EE increase the serum concentration of sex hormone-binding globulin threefold free testosterone levels by 50%

Cycle control, Contraception. 2002 Dec.

Clinical comparative study of oral contraceptives containing 30 mcg ethinylestradiol/150 mcg levonorgestrel (LNG), and 35 mcg ethinylestradiol/250 mcg Norgestimate (NGM) in Thai women

35 mcg EE/250 mcg NGM provides reliable contraceptive efficacy. It also provides good cycle control equal to 30 mcg EE/150 mcg LNG with a lower incidence of minor adverse effects such as headache and dizziness compared to 30 mcg EE/150 mcg LNG.

CVD Risk, Mymensingh Med J. 2006 Jul.

Risk of cardiovascular diseases with oral contraceptives

Cardiovascular diseases occur mainly among oral contraceptive users who smoke or have predisposing factors–such as age more than 35 years, overweight, diabetes & hypertension.

Bleeding patterns, Fertil Steril. 2009 Aug.

Scheduled and unscheduled bleeding patterns with two combined hormonal contraceptives: application of new recommendations for standardization

The NGM 250 mcg/EE 35 mcg has a lower incidence and comparable length of unscheduled bleeding and a higher incidence of scheduled bleeding than NETA/EE 200 mcg in this post hoc analysis.

Perfect Use Pearl index, Trussell J. Contraceptive Efficacy. In: Hatcher RA, et al (eds). Contraceptive Technology. 19th rev. ed. Ardent Media, New York, 2007.

The number for use under perfect conditions. The perfect use pregnancy rate of combined oral contraceptive users (COC) is 0.3% per year.

User effectiveness or typical effectiveness

The Pearl index number for use is not consistent or always correct. The typical use pregnancy rate among COC users varies depending on the population being studied, ranging from 2– 8.6% per year.

Audet MC, Moreau M, Koltun WD, Waldbaum AS, Shangold G, Fisher AC, Creasy GW. Evaluation of contraceptive efficacy and cycle control of a transdermal contraceptive patch vs an oral contraceptive: a randomized controlled trial. JAMA 2001.
Fu H, et al., Contraceptive failure rates: new estimates from the 1995 National Survey of Family Growth, Family Planning Perspectives 1999.
Hatcher RA, Trussell J, Stewart FH. Contraceptive Technology. 18th ed. Ardent Media, New York; 2004.

Metabolic effects and side effects, Acta Obstet Gynecol Scand Suppl. 1992

A comparison study of lipid and androgen metabolism with oral contraceptive formulations containing norgestimate or levonorgestrel

In a study of 66 healthy women treated through six menstrual cycles
Cholesterol and its subtractions, triglycerides, carrier lipoproteins, estradiol, testosterone, and sex hormone-binding globulin (SHBG). Comparison of baseline values with values after 3 and 6 months of treatment indicated that both regimens influenced lipid and androgen metabolism.
Related data on SHBG showed that its plasma levels as an indicator of estrogen/androgen balance were increased significantly more in the norgestimate group, providing additional evidence of low androgenicity.
The results of the study support the reported safety and positive effects of norgestimate on lipid and androgen metabolism, in comparison with a levonorgestrel-containing combined OC.

HDL/LDL ratio Vs Gestodene,

Burkman RT, Kafrissen ME, Olson W, Osterman J. Acta Obstet Gynecol Scand 1992

Lippman J. Int J Fertil 1992. In a meta-analysis of more than 50 prospective trials

Gestodene’s lipid adverse effects were minimal (e.g., small increases in triglycerides and phospholipids),” but norgestimate, having no significant androgenicity, improved the lipid profile by increasing the HDL/LDL ratio.39,41

Clinical efficacy, Acta Obstet Gynecol Scand Suppl.1990, U.S. clinical trials

Two long-term, multicentric clinical trials demonstrate that this formulation is comparable in efficacy to the 2^nd Gen OCs.

There were no statistically significant differences in pregnancy rate, and both OCs were well-tolerated in a large and diverse study population.
Lower androgenicity of the (ESTRACEPTIVEÒ), EE/NGM OC produced clinical changes that were primarily evident in:
The more natural menstrual patterns
Its less severe impact on the endometrium
And, most importantly, its positive impact on lipoprotein metabolism.
ESTRACEPTIVEÒ, EE/NGM consistently produced statistically significant increases in high-density lipoprotein (HDL) and concomitant improvement in the ratio of low-density lipoprotein (LDL) to HDL. By cycle 24.
This highly predictive parameter of atherosclerotic risk HDL/LDL ratio had decreased in the NGM/EE group by 7%.
Conversely, the 2nd Gen OCs -containing formulation resulted in statistically significant decreases in HDL and increases in the LDL/HDL ratio; by cycle 24, these patients showed a 5% increase in the LDL/HDL ratio.

Androgenic and estrogenic properties Biochem Biophys Res Commun. 2017 Sep

Comparing the androgenic and estrogenic properties of progestins used in contraception and hormone therapy

Some progestins may result in side effects including increased risk of developing breast cancer, cardiovascular disease, venous thromboembolism, and increased susceptibility to genital tract infections. Some of these adverse effects may be attributed to off-target actions via steroid receptors other than the PR
Gestodene among binds to human Estrogen receptor ERα, but not human ERβ, and are ERα agonists for both transactivation and transrepression
GES bioavailability is approximately 25% and may compete with estrogen for binding to ERα in target tissues.

Non-contraceptive health benefits

These benefits are not FDA-approved indications, but more like a clinical experience:

Reduction in the amount of monthly blood loss resulting from a progestin “antiestrogenic” action on the endometrium. In the anovulatory cycle, the mean blood loss is about 35 mL, compared with 20 mL in OC users. OCs are often an effective treatment for menorrhagia.
Less iron-deficiency anemia.
Fewer menstrual irregularities: OCs are designed to produce regular withdrawal bleeding.
Lowered risk of endometrial cancer. OC use for 1 year reduces the risk by 40% (94) and by 80% after 10 years of use.
Lowered risk of ovarian cancer. Risk is reduced by 40% (97) after ever-use and 80% reduced after 10 years of use.
Lowered risk of benign breast disease. Reduced risk of cysts, fibrocystic changes, fibroadenomas. Progestins inhibit the synthesis of estrogen receptors in breast tissue.
Less dysmenorrhea (63%). use can reduce absences from work or school.
Lowered incidence of symptomatic endometriosis.
Less premenstrual syndrome symptoms (29%).
Less bloating, pain, cramping, mastalgia.
Lowered incidence of androgen excess conditions. Reduction in acne lesions and hirsutism.
Thickened cervical mucus preventing the movement of sperms carrying pathogens into the uterus.
Reduction in hot flashes and other perimenopausal symptoms

Precautions and Practice guidelines

Smoking.

In combination with oral contraceptive use has been shown to contribute substantially to the incidence of myocardial infarctions in women in their mid-thirties or older with smoking accounting for the majority of excess cases.

Mortality rates associated with circulatory disease have been shown to increase substantially in smokers, especially in those 35 years of age and older, and in nonsmokers over the age of 40 among women who use oral contraceptives.

Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, combination oral contraceptives, including EE/NGM, should not be used by women who are over 35 years of age and smoke.

Thromboembolism

An increased risk of thromboembolic and thrombotic disease associated with the use of oral contraceptives is well established. Case-control studies have found the relative risk of users compared to nonusers to be:

3 for the first episode of superficial venous thrombosis,
4 to 11 for deep vein thrombosis or pulmonary embolism,
5 to 6 for women with predisposing conditions for venous thromboembolic disease.

Cohort studies have shown the relative risk to be somewhat lower, about 3 for new cases and about 4.5 for new cases requiring hospitalization.

The risk of thromboembolic disease associated with oral contraceptives is not related to the length of use and disappears after pill use is stopped.

A two- to four-fold increase in relative risk of postoperative thromboembolic complications has been reported with the use of oral contraceptives.

The relative risk of venous thrombosis in women who have predisposing conditions is twice that of women without such medical conditions.

Since the immediate postpartum period is also associated with an increased risk of thromboembolism, oral contraceptives should be started no earlier than four weeks after delivery in women who elect not to breastfeed.

Other generalized risk factors for venous or arterial thromboembolism include but are not limited to:

Age
Severe obesity (body mass index >30 kg/m2)
Personal history, a positive family history (the occurrence of VTE/ATE in a direct relative at a relatively early age may indicate genetic predisposition), and systemic lupus erythematosus. If a hereditary or acquired predisposition for venous or arterial thromboembolism is suspected, the woman should be referred to a specialist for advice before deciding on any COC use.
The risk of VTE/ATE may be temporarily increased with prolonged immobilization, major surgery, or trauma. In these situations, it is advisable to discontinue COC use (in the case of elective surgery at least four weeks in advance) and not to resume COC use until 2 weeks after complete remobilization.
Also, patients with varicose veins and leg casts should be closely supervised. Other risk factors may include smoking (with heavier smoking and increasing age, the risk further increases, especially in women over 35 years of age), dyslipidemia, hypertension, migraine, valvular heart disease, and atrial fibrillation.
Biochemical factors that may be indicative of hereditary or acquired predisposition for venous or arterial thrombosis include Activated Protein C Resistance (APCR) and other coagulation factors deficiency.

Cerebrovascular Diseases

Oral contraceptives have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years) hypertensive women who also smoke.
Hypertension was found to be a risk factor for both users and nonusers, for both types of strokes, and smoking interacted to increase the risk of stroke. In a large study, the relative risk of thrombotic strokes has been shown to range from 3 for normotensive users to 14 for users with severe hypertension.
The relative risk of hemorrhagic stroke is reported to be:
2 for non-smokers who used oral contraceptives
6 for smokers who did not use oral contraceptives
6 for smokers who used oral contraceptives,
8 for normotensive users
7 for users with uncontrolled severe hypertension.
The attributable risk is also greater in older women.
Predisposing Factors for Coronary Artery Disease
Cigarette smoking
Age > 35
Several cigarettes were smoked.
For this reason, COCs, including Estraceptive®, should not be used by women who are over 35 years of age and smoke.
In low-risk, non-smoking women of any age, the benefits of oral contraceptive use outweigh the possible cardiovascular risks associated with low-dose formulations. Consequently, oral contraceptives may be prescribed for these women up to the age of menopause.

Myocardial Infarction

An increased risk of myocardial infarction has been attributed to oral contraceptive use. This risk is primarily in smokers or women with other underlying risk factors for coronary artery disease such as hypertension, hypercholesterolemia, morbid obesity, and diabetes. The relative risk of heart attack for current oral contraceptive users has been estimated to be two to six. The risk is very low under the age of 30.
Norgestimate has minimal androgenic activity and there is some evidence that the risk of myocardial infarction associated with oral contraceptives is lower when the progestogen has minimal androgenic activity than when the activity is greater.

Diabetes

Current low-dose oral contraceptives exert minimal to no impact on glucose metabolism.
Diabetic patients, or those with a family history of diabetes, should be observed closely to detect any HbA1c deviation.
Patients predisposed to diabetes who can be kept under close supervision may be given oral contraceptives.
Young, newly diabetic patients, well-controlled, and not associated with hypertension or other signs of vascular disease, should be monitored more frequently while using oral contraceptives.

Dyslipidemia

Disease from Oral Contraceptives A positive association has been observed between the amount of estrogen and progestogen in oral contraceptives and the risk of vascular disease.
A decline in serum high-density lipoproteins (HDL) has been reported with many progestational agents (not Estraceptive®). which has been associated with an increased incidence of ischemic heart disease.
Because estrogens increase HDL cholesterol, the net effect of an oral contraceptive depends on a balance achieved between doses of estrogen and progestogen and the activity of the progestogen used in the contraceptives.

The activity and a balanced amount of both hormones should be considered in the choice of an oral contraceptive.

Elevated Blood Pressure

Women with significant uncontrolled hypertension should not be started on hormonal contraception.
An increase in blood pressure has been reported in women taking some oral contraceptives and this increase is more likely in older oral contraceptive users or contraceptives with very high PR.
Data from the Royal College of General Practitioners and subsequent randomized trials have shown that the incidence of hypertension increases with increasing progestational activity.
Women with a history of hypertension or hypertension-related diseases or renal disease should be encouraged to use a safer oral combination or another method of contraception.
They should be monitored closely and if a clinically significant persistent elevation of blood pressure (BP) occurs (³ 160 mm Hg systolic or ³ 100 mm Hg diastolic) and cannot be adequately controlled, oral contraceptives should be discontinued.
In general, for women who develop hypertension during hormonal contraceptive therapy, hormonal contraceptive therapy may continue combined with antihypertensive therapy.
It should be noted that in two separate large clinical trials (N=633 and N=911), no statistically significant changes in mean blood pressure were observed with EE/NGM(Estraceptive®).

Bleeding Irregularities

Breakthrough bleeding and spotting are sometimes encountered in patients on oral contraceptives, especially during the first three months of use.
Non-hormonal causes should be considered and adequate diagnostic measures are taken to rule out malignancy or pregnancy in the event of breakthrough bleeding, as in the case of any abnormal vaginal bleeding.
If pathology has been excluded, time or a change to another hormonal-balanced formulation may solve the problem.
Using an oral contraceptive with a balanced estrogen content, while potentially useful in minimizing menstrual
In the event of amenorrhea, pregnancy should be ruled out. Some women may encounter post-pill amenorrhea or oligomenorrhea, especially when such a condition was preexistent.
Higher incidence during the first three OC cycles. Cycle problems tend to lessen within a few months of OC initiation, regardless of formulation. Strategies for dealing with cycle problems include: informing the women that these problems tend to decrease during the first 3 months of use and that they should not discontinue or change the formulation during this period; consideration of factors that can contribute to problems, such as missed doses, chlamydial infections, smoking, and interacting medications; changes in the regimen (adding estrogen or decreasing progestin if bleeding occurs early in the cycle, adding progestin if it occurs late in the cycle, or doubling active pills until the bleeding stops or for the rest of the cycles); or providing a course of non-steroidal anti-inflammatory drugs.

Weight Gain

Although controversial, weight gain is thought to result from the progestin component in combination OCs, but others attribute weight gain to psychological factors.
However, Estraceptive® did not cause any significant changes in body weight when administered to more than 8000 women for at least 6 cycles

Follow-Up

Physical Examination and Follow-up It is a good medical practice for all women to have annual history and physical examinations, including women using oral contraceptives. The physical examination should include special reference to blood pressure, breasts, abdomen, and pelvic organs, including cervical cytology, and relevant laboratory tests.
Liver Function. if jaundice develops in any woman receiving such drugs, the medication should be discontinued. Steroid hormones may be poorly metabolized in patients with impaired liver function.
Fluid Retention. Oral contraceptives may cause some degree of fluid retention. They should be prescribed with caution or replaced by safer
Emotional Disorders. Women with a history of depression should be carefully observed and the drug discontinued if depression recurs to a serious degree.