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The "natural estrogens" containing pills Imprimer
Analyses scientifiques

50th anniversary of the contraceptive pill celebrated on May 9, 2010


and...the first days for the first estradiol contraceptive pill.

Hard for a lot of people to believe the birth control pill has been around now for half a century. It became a game changer for millions of American women and for American society. May 9 was not only Mother's Day - it was also the 50th anniversary of "The Pill," the oral contraceptive birth control. Like it or not, the arrival of the birth control pill was a momentous occasion in human civilization and has an enormous social impact.The pill also has been credited - or blamed - for overturning sexual mores, but there is less evidence that it caused or evenly greatly contributed to the sexual revolution. The world  experienced sharp changes in sexual behaviour in the 1920s, during World War II, and during the 1960s and '70s.Other predictions swirling around at the time of its debut did not come true. The pill did not curb worldwide population growth, create happier sex lives for married couples or reduce rates of divorce. Today, an estimated 12 million American women use the pill and about 80% will use it at some point in their reproductive lives. Yet, just because it's readily available doesn't mean it's always easy to get. The FDA   approved the first pill in the first year of the Swinging Sixties, but the pill did not spark the sexual revolution. Nor did it cause a sudden drop in the   fertility rate, which didn't bottom out until the early 1970s." Nevertheless, the pill's influence has been lasting and pervasive. It became a symbol of women's rights and generational change -- and, for a time, the focus of a debate over whether it led to declining morals.

Yet, women became dependent on doctors for contraception, because the pill was, and still is, available only with a prescription." Some women's advocates argue that pills today are much safer; therefore, they should be available without a prescription.

The Food and Drug Administration has given on May 7, 2010, its approval to Natazia, (also termed Qlaira in Europe), a novel birth control pill from Bayer Healthcare that combines  the hormones estrogen and progestin in doses that adjust four times throughout a woman's period cycle. The pill is the first birth control product to u

se four-phase dosing, according to the FDA.

Natazia is the first oral contraceptive to use a synthetic estrogen called estradiol valerate in combination with a progestin called dienogest. Other birth control pills contain ethinyl estradiol as an estrogen.

The drug also may offer a new treatment option for women who suffer from heavy or prolonged menstrual periods, Bayer said in October after presenting clinical trial data in which the drug, compared to placebo, reduced menstrual bleeding in a study of 231 women over the course of 90 days.

The drug was evaluated by more than 1,800 women during clinical testing in North America and Europe". The most common adverse effects were irregular bleeding, breast tenderness, headache, nausea and vomiting, weight gain, and acne. The FDA warned that women older than 35 who smoke should not use the product, because it could put them at risk for potentially serious cardiovascular problems.

The "natural estrogens" containing pills

By Nathalie Chabbert-Buffet (France)

The development of oral contraception has been one of the great medical and social revolutions of the last century. Oral contraception is one of the most used techniques in many countries. As defined by the WHO, contraception must be efficient, reversible, affordable and well tolerated. In this perspective, the potential impact of the use of estrogens and progestins  for contraception has been a subject of controversy for the last 10 to 15 years, especially concerning (arterial and venous) vascular risk as well as carcinologic risk.

Different generations of oral contraceptives (OCs) have been developed mainly  to reduce the metabolic and vascular risk .  The most recent,  third generation oral contraceptives (OC), are an association of low dose ethinyl estradiol and potent testosterone related progestins, developed to improve general and vascular tolerance. They are highly efficient and well tolerated by most users. Their extensive use has provided different key information: OCs (and non oral ethinyl estradiol containing contraceptives) can be used in women under the age of 35 with well controlled metabolic risk factors and high familial risk of breast cancer. On the other hand ethinyl estradiol containing contraceptives are not indicated  in women with a high  risk of deep venous thrombosis, or non controlled metabolic and vascular risk factors (including age over 35 and cigarette smoking), or with a history of breast cancer. Progestin only contraception is not well tolerated due to bleeding.

The current hormonal contraception concepts contain "non testosterone-derived" progestins and "non ethinylated" estradiol.

Three type of such contraceptives are currently under development at different stages. The association of estradiol valerate and Dienogest has been launched in September 2009 in Europe. The association of estradiol and  nomegestrol acetate is currently in phase 3 studies. The product has been submitted at the EMEA and it should be launched  in 2010. Finally the association of estetrol (a placental estrogen) with different progestins is evaluated in phase 1 studies.

In this contraceptive concept the progestin is the antigonadotropic actor. This includes the need for relativement high doses of the progestin. The estrogen is added in order to avoid side effects of antigonadotropic progestins such as bleeding, vaginal dryness,  and bone mineral density reduction.

The use of estradiol instead of ethinyl estradiol allows a dramatic reduction of the estrogenic activity. This reduction is related to the lower affinity for the estrogens receptor, a reduced number of enterohepatic cycles and a faster metabolization and excretion of  inactive  metabolites.  It will thus reduce the impact on the different hepatic protein currently used as markers of metabolic and vascular risk. However data from the ESTHER study, conducted in post menopausal women, have shown that the risk of DVT still exists when estradiol is administered orally.

The use of nomegestrol acetate (NOMAC) as a progestin  will allow a high progestogenic activity as well as a reduction in the impact of progestins on risk markers.   NOMAC is a 19 nor progesterone derivative (or nor pregnane)   which has a high bioactivity, related to its structure. The association of the suppression of the radical at carbone 19 (summarized as "nor" for no radical in the norpregnane  name), of a double bound between carbon 6 and 7, as well as  a modification of the substitution at carbon 17 leads to a high affinity for the progesterone receptor, the absence of affinity for SHBG (a high affinity steroid carrier protein)  and a low affinity for both the androgen and the glucocorticoid receptors .

Clinical studies conducted on small numbers of women using NOMAC alone have shown that this molecule is able to block the LH surge as well as the FSH intercycle rise for doses of .5 mg/d or more, allowing anovulation in all women.The metabolic tolerance was good in normal women using NOMAC alone, as well as in women with dyslipidemia.  Markers of thrombosis were not modified.

Phase II studies evaluating the effect of the association of NOMAC and estradiol 1.5 mg/d  (NOMAC E2) have confirmed that the association also induced anovulation provided that the dose of NOMAC was 2.5 mg/d or  higher. Interestingly the association showed some  synergy in down regulating FSH and LH as compared to NOMAC alone (presented at the European Society of Gynecology congress 2009 in   Rome). Furthermore the  scheme of administration of  NOMAC E2  24days /28 showed to be more efficient than the same association administered 21 days/28 (presented at the FIGO congress 2009 South Africa).

Unpublished phase III studies compared the association of NOMAC  (2.5 mg/d)E2 (1.5 mg/d)  24 days /28  with the association ethinyl estradiol (30 µg/d) and drospirenone. The rates of pregnancy were lower, no matter the calculation technique, in the NOMAC E2 group. Bleeding patterns were comparable. The increase in SHBG was 33% in average.

These results provide  evidence that the association of NOMAC (2.5 mg/d) with estradiol (1.5 mg/d) administered 24 d/28 is efficient for contraception and well tolerated.

This association will be indicated for women without a contra indication to oral contraceptives. It  is not targeting high risk women.



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