Conjugated Estrogens


Action And Clinical Pharmacology: Conjugated estrogens are a mixture of estrogens derived from plant sterols and contain the sodium salts of water-soluble estrogen sulfates. C.E.S. is derived from plant sterols, only. Conjugated estrogens contain estrone, equilin, 17-a-dihydroequilin, 17-a-estradiol, equilenin and 17-a-dihydroequilenin as salts of their sulfate esters.

Actions: Metabolic and Somatic Effects: Estrogens are responsible for the development and maintenance of the female reproductive system and secondary sex characteristics. Estrogens cause growth and development of the vagina, uterus and fallopian tubes, and the enlargement of the breasts. Indirectly, estrogens contribute to the shaping of the skeleton, maintenance of tone and elasticity of urogenital structures, cause changes in the epiphyses of the long bones producing pubertal growth spurt and termination, axillary and pubic hair growth, and pigmentation of the nipples and genitals. Estrogens affect calcium and phosphorus metabolism and are involved in maintaining normal bone structure. In prolonged estrogen deficiency states, the administration of estrogens may alter associated degenerative bone changes.

Effect on Menstruation: An ebb and rise of the female gonadal hormone produces the normal menstrual cycle. In the pre- and anovulatory cycle, estrogens are the primary determinants for the onset of menstruation. Estrogens do not induce ovulation. Estrogen levels rise during the first half of the menstrual cycle. At midpoint in the second half of the cycle, the corpus luteum produces high levels of both estrogens and progesterone. Decline of estrogenic activity at the end of the menstrual cycle commonly brings on menstruation, although the cessation of progesterone secretion is the most important factor in this phase of the mature ovulatory cycle.

Effects on Nervous System: Estrogens also affect the psychologic and emotional aspects of feminine behavior. As estrogen levels increase during the menstrual cycle, women experience a sense of well-being and vigor. In the postmenopausal period, after the decline of endogenous estrogen production, estrogen administration aids in relieving nervous symptoms, such as anxiety, depression and irritability.

Indications And Clinical Uses: Replacement therapy in naturally occurring or surgically induced estrogen deficiency states associated with the climacteric, including the menopausal and postmenopausal syndromes; senile vaginitis and kraurosis vulvae, with or without pruritus; female hypogonadism; amenorrhea; primary ovarian failure; and for estrogen deficiency-induced osteoporosis, when combined with other important therapeutic measures such as a diet, calcium, physiotherapy, and good general health-promoting measures. For abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathologic changes such as submucosal fibroids or uterine cancer. For inoperable progressing prostatic cancer (for palliation only when castration is not feasible, or when castration failures or delayed escape following a response to castration have occurred); breast cancer (for palliation only in women more than 5 years past the menopause with progressing inoperable or roentgen-resistant disease).

Contra-Indications: Should not be administered to patients with active hepatic dysfunction or disease, especially of the obstructive type; or a personal history of breast or endometrial cancer, except in special circumstances.

Endometrial hyperplasia is also a contraindication for estrogen therapy without accompanying progestogen.

Also contraindicated in the following situations: undiagnosed vaginal bleeding; a history of cerebrovascular accident, coronary thrombosis or in the presence of classical migraine; a history of thrombophlebitis or thromboembolic disease; partial or complete loss of vision or diplopia due to ophthalmic vascular disease; when pregnancy is suspected.

Manufacturers’ Warnings In Clinical States: Before conjugated estrogen is administered, the patient should have a complete physical examination including a blood pressure determination. Breast and pelvic organs should be examined and a Papanicolaou smear should be taken.

The first follow-up examination should be done preferably within 6 months after initiation of treatment. Thereafter, examinations should be made once a year. At each annual visit, examination should include those procedures outlined above that were done at the initial visit.

If any surgical procedures are performed, the pathologist should be advised of the patient’s therapy when specimens are sent for examination. Liver function tests should be made periodically in subjects who have, or are suspected of having, hepatic disease.

If abnormal vaginal bleeding occurs during therapy, suction aspiration or curettage should be performed to rule out the possibility of uterine malignancy.

Although the estrogen content of oral contraceptive therapy has been associated with an increased risk of various thromboembolic, thrombotic and vascular diseases, to date no such increased risk in postmenopausal users of estrogens has been detected. Nevertheless, the physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, retinal thrombosis, cerebral embolism, and pulmonary embolism). If these occur or are suspected, estrogen therapy should be discontinued immediately.

In patients with metastatic carcinoma and hypercalcemia, estrogen medication should be used with caution. Three independent retrospective studies have reported an association between postmenopausal oral estrogen therapy and an increased risk of endometrial carcinoma. These studies however, lacked information regarding certain important intrinsic risk factors of the patients (especially pretreatment endogenous hormonal status) and the mode of administration of estrogen. The potential relationship of estrogen to endometrial carcinoma under clinical conditions has to be considered. However, a cause and effect relationship between estrogen administration and endometrial carcinoma cannot be established by these data at this time.

Precautions: Development of sudden enlargement, pain, or tenderness of uterine fibroid requires discontinuation of medication.

Estrogen may cause sodium and water retention. Where this may be undesirable such as in cardiac or renal dysfunction, epilepsy, or asthma, particular caution is indicated.

Elevation of blood pressure in previously normotensive or hypertensive patients necessitates cessation of medication.

Diabetic patients or those with a predisposition to diabetes should be observed closely to detect any alterations in carbohydrate metabolism.

When liver or endocrine function tests are indicated, the results should not be considered reliable unless therapy has been discontinued for 2 to 4 months.

Adverse Reactions: The following adverse reactions have been reported with the use of estrogens in general. Some of these (indicated in brackets) have been documented with oral contraceptives specifically, and have not, up to now, been associated with cyclic menopausal or postmenopausal conjugated estrogen therapy.

Gastrointestinal: nausea, (anorexia, vomiting, abdominal cramps, bloating), cholestatic jaundice and increase in body weight.

Genitourinary: sodium and water retention, breakthrough bleeding, spotting and withdrawal bleeding, increased cervical mucus, endometrial hyperplasia, reactivation of endometriosis, (cystitis-like syndrome).

Endocrine and Metabolic: breast swelling and tenderness, increased blood sugar levels, and decreased glucose tolerance. If product is indicated in males add: gynecomastia, reduced potency and feminization.

CNS: headaches, mental depression, increase or decrease of libido, (mental depression, nervousness, dizziness, fatigue, irritability).

Dermatologic – Hypersensitivity: allergic reactions and rashes, chloasma, (hemorrhagic eruption, itching, erythema nodosum, and erythema multiforme, pigmentation of the skin, loss of scalp hair).

Cardiovascular: an increase in blood pressure in susceptible individuals and aggravation of migraine headaches.

Hematologic: A statistically significant association has been demonstrated between the use of oral contraceptive preparations containing estrogens and the following serious reactions: thrombophlebitis, pulmonary embolism and cerebral thrombosis. Although available evidence is suggestive of an association, such a relationship has been neither confirmed nor refuted for the following serious reactions: coronary thrombosis and neuro-ocular lesions (e.g., retinal thrombosis and optic neuritis); altered coagulation tests (increase in prothrombin and Factors VII, VIII, IX, X).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Excessive doses may result in nausea, vomiting and abdominal cramps, headaches, dizziness and general malaise. All of the ingested drug should be removed by gastric lavage and symptomatic treatment given.

Dosage And Administration: In general, estrogen should be given cyclically (21 to 25 days followed by a 5 to 7 day rest period) and in some cases with progestogen or androgen to avoid overstimulation of breast and endometrial tissues. The addition of sufficient progestogen to promote conversion of the endometrium is mandatory in those patients who are receiving sufficient unopposed estrogen to cause vaginal bleeding or endometrial hyperplasia. Obviously, abnormal vaginal bleeding in such patients is an indication for prompt diagnostic measures.

The dosage should be carefully adjusted to the individual needs of the patient, the lowest effective dosage should be used, and the requirement for estrogen therapy should be reassessed periodically.

Menopausal Symptoms: 0.3 to 1.25 mg daily, cyclically. Adjust dosage upward or downward according to severity of symptoms and response of the patient. For maintenance, adjust dosage to lowest level providing effective control. If the patient has not menstruated within the last 2 months or more, cyclic administration is started arbitrarily. If the patient is menstruating, cyclic administration is started on day 5 of bleeding. If breakthrough bleeding (bleeding or spotting during estrogen therapy) occurs, the C.E.S. dosage should be increased as needed to stop bleeding. In the following cycle, the same dosage should be administered as that used to stop breakthrough bleeding in the previous cycle. In subsequent cycles, the dosage should be gradually reduced to the lowest level which will maintain the patient symptom-free. If planned withdrawal bleeding is desirable, a progestogen may be added during the last 5 to 10 days of the usual recommended C.E.S. regimen.

Postmenopause: For the treatment of estrogen deficiency-induced degenerative changes (e.g., osteoporosis, atrophic vaginitis, kraurosis vulvae): 0.3 to 1.25 mg daily and cyclically. Adjust dosage to lowest effective level.

Hypogenitalism: In an attempt to attain sexual and somatic maturation: 2.5 to 7.5 mg daily, in divided doses for 21 days, followed by a rest period of 10 days’ duration. If bleeding does not occur at the end of this period, the same dosage schedule is repeated. The number of courses of C.E.S. therapy necessary to produce bleeding may vary depending on the responsiveness of the endometrium. If bleeding occurs before the end of the 10-day period, a 20-day C.E.S.-progestogen cyclic regimen, as in amenorrhea, is recommended.

Amenorrhea: To reproduce the hormone pattern of the ovary, i.e., bleeding from a progestational endometrium, begin a 20-day C.E.S.-progestogen cyclic regimen: 2.5 to 7.5 mg daily in divided doses, for 20 days. During the last 5 days of estrogen therapy, oral progestogen is added. If bleeding occurs before this regimen is concluded, therapy is discontinued and may be resumed on the fifth day of bleeding.

Mammary Carcinoma: (for palliation in women with progressive inoperable or roentgen-resistant disease more than 5 years after the menopause) suggested dosage: 10 mg 3 times daily for a period of at least 3 months.

Prostatic Carcinoma: (for palliation when castration is not feasible or when castration failure or delayed escape has occurred: suggested dosage: 1.25 to 2.5 mg 3 times daily). The effectiveness of therapy can be judged by phosphatase determination as well as by symptomatic improvement of the patient.

Availability And Storage: 0.3 mg: Each oval, green tablet contains: conjugated estrogens CSD 0.3 mg. Nonmedicinal ingredients: calcium phosphate, colloidal silicon dioxide, lactose, magnesium carbonate, microcrystalline cellulose, starch and stearic acid. Bottles of 100.

0.625 mg: Each oval, maroon tablet contains: conjugated estrogens CSD 0.625 mg. Nonmedicinal ingredients: calcium phosphate, colloidal silicon dioxide, lactose, magnesium carbonate, microcrystalline cellulose, starch and stearic acid. Bottles of 100 and 1 000.

0.9 mg: Each oval, pink tablet contains: conjugated estrogens CSD 0.9 mg. Nonmedicinal ingredients: calcium phosphate, colloidal silicon dioxide, lactose, magnesium carbonate, microcrystalline cellulose, starch and stearic acid. Bottles of 100.

1.25 mg: Each oval, yellow tablet contains: conjugated estrogens CSD 1.25 mg. Nonmedicinal ingredients: calcium phosphate, colloidal silicon dioxide, lactose, magnesium carbonate, microcrystalline cellulose, starch and stearic acid. Bottles of 100 and 1 000.

C.E.S.® ICN Conjugated Estrogens Estrogens

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