Metabolic effects of mestranol in high dosage

METABOLIC EFFECTS OF MESTRANOL IN HIGH DOSAGE

Anne C. Carter, Benjamin Slivko and Elaine B. Feldman From the Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, N.Y.

Received:

February 9, 1970 ABSTRACT

Metabolic effects of mestranol, given in continuous high dosage for 3 or more months, were investigated in 4 postmenopausal women with metastatic breast cancer. Three women improved subjectively; in i patient objective remission of disease occurred. Adverse effects included: peripheral edema, weight gain of variable duration, hypertension, pruritus, increased skin pigmentation. In i patient, at i and 2 months of treatment, bromsulphthalein retention occurred; serum bilirubin, glutamic-oxalacetic transaminase and alkaline phosphatase levels were increased transiently. These values returned to normal by 4 months, and remained normal for almost 3 years of treatment. With treatment, average values of plasma cholesterol were increased slightly, phospholipid levels were 20% greater, and triglycerides increased 40%. Circulating free fatty acid levels were decreased. Plasma alpha-lipoprotein increased by 40%. Blood sugar values were less. Plasma cortisol increased greatly; plasma growth hormone increased 3-fold: urinary gonadotrophin excretion diminished. There was a modest increase in serum protein-bound iodine values; thyroxine-binding globulin capacity doubled. A confusing variety of "toxic" and metabolic consequences of contraceptive "pills" has been reported (1-5).

The causes of "adverse"

effects cannot be determined readily because of different dosages, combinations of estrogenic and/or progestational components in various preparations,

and possible impurities of the various "pills".

This

study was carried out to determine toxicity and metabolic effects of long-term continuous administration of mestranol 1,3,5(10)trien-3,17

B-diol-3-methylether,

(17~-ethinyl-estra-

NSC-84032)

in a large dose

to post-menopausal women prior to subsequent evaluation of'the drug in the treatment of patients with metastatic breast carcinoma.

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MATERIALS AND METHODS Four postmenopausal women, 55, 61, 61 and 73 years old (Table I) were given mestranol, i mg three times a day, for 5, 6, 9, and 36 months. The patients had metastatic breast carcinoma, classified as pulmonary disease (3 women), or local (i patient) tumor involvement (6). All patients had been treated previously for progressive metastatic breast cancer with either D-homotestosterone propionate, NSC-35750 (i patient), 2-~-methyldihydrotestosterone propionate, NSC-12198 (i patient), 7~-methyl-19-nortestosterone acetate, NSC-69948 (2 patients). Medication had been discontinued 2, 3, 22 and 34 months before the present study. The body weights of the women were within 10% of ideal for their heights and ages. None of the women had a family history of diabetes mellitus. All patients were ambulatory. Patients were examined initially and at monthly intervals. Body height and weight, temperature, pulse, blood pressure were measured. Patients were asked to report presence, absence and degree of urinary symptoms, vaginal discharge, libido, itching, skin rash, nausea or vomiting. On examination, presence of edema, or skin pigmentation was noted. Vaginal smear, hemogram and urine analysis were performed. Blood studies were obtained initially, and at approximately monthly intervals, between 8 and 9 a.m., after an overnight fast. The studies from the routine clinical laboratories of Kings County Hospital included: serum bilirubin, glutamic-oxaloacetic transaminase, albumin, globulin, thymol turbidity, cephalin flocculation, bromsulphthalein retention, blood urea nitrogen and glucose, prothrombin time. Serum calcium (7), phosphorus (8), alkaline phosphatase (9), protein-bound iodine (i0), thyroxine-binding globulin capacity (ii), plasma cortisol (12), insulin and growth hormone (13), cholesterol (14), triglycerides (15), phospholipids (16), free fatty acids (17), lipoproteins (18); red blood cell uptake of triiodothyronine (19) were analyzed in the research laboratories of the authors. Twenty-four hour urine collections were analyzed for creatinine (20), 17-ketosteroids, 17-ketogenic steroids (21) and total gonadotrophins by ovarian weight (22). Response of tumor to therapy was evaluated by clinical examination, measurements and photographs of visible and palpable tumor masses, and radiographs. RESULTS WITH TREATMENT Clinical observations

during treatment are detailed in Table i.

Three women improved subjectively; of disease also occurred.

objective remission

Two women are still alive 23 and 5 months

after treatment was stopped. One patient was nauseated.

in one patient,

Appetite increased in two women. Two women developed peripheral e d e m a :

one woman maintained an 8 lb. weight gain throughout treatment; the other woman gained 3 ibs. and then lost 17 ibs. siently gained 8 ibs. without edema.

One woman tran-

One patient each noted pruri-

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TABLE i Clinical Data of Patients given Mestranol

Age, yrs. Treatment Improvement Survival Appetite Nausea Edema Weight, ibs. Pruritus Pigmentation BP elevation,

C

D

M

S

61 36 mo. subjective objective 5 mo.

61 308 days

55 114 days

73 169 days

subjective 23 mo. + + + 165-168-151

subjective *4½ mo. +

*2 mo.

128-136-128

109-93

20/20

5/0

+ 155-163

+ (9 mo.) + (8 mo.) 60/30

20/10

*Deceased

tus and increased skin pigmentation after taking drug for 9 and 8 months respectively.

Systolic and diastolic blood pressure in-

creased about 20 mm in all patients.

A moderate to strong estro-

gen effect was apparent in all vaginal smears examined. globin (Hgb) and hematocrit cantly with treatment

Hemo-

(Hct) values did not change signifi-

(Table 2).

Mean white blood cell count

increased from ll,030/rmn 3 to 15,324/mm 3, and the proportion of segmented neutrophils

increased from 68% to 78%.

Many blood chemical values were unchanged at all times throughout the treatment period. serum proteins,

cephalin flocculation

turbidity, phosphorus, (BUN)

(Table 2).

These tests included: (Ceph flocc), thymol

prothrombin time, and blood urea nitrogen

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TABLE 2 Average Values of Studies during Mestranol Treatment Test

Total Protein, gm/100 ml Ceph flocc Thymol turbidity Phosphorus, mg/i00 ml BUN, mg/100 ml Hgb, gm/100 ml Hct, % Prothrombin time, seconds

Pre-therapy

With Therapy

No.

Mean

Range

7.3 + i

23 23 19

7.3 + i

(4.5-9.3) (0-2+) (1-4)

3.75 18 12.0 37 12.0

25 21 28 28 5

3.35 18 11.6 36 12.3

(2.40-4.79) (10-29) (8.8-13) (30-47) (12-13)

With other tests of liver function, mean values for patients under treatment were unchanged from pre-treatment levels (Table 3). TABLE 3 Blood Tests with Transient Abnormalities during Treatment with Mestranol Test

Alk p'tase, Bodansky U Bilirubin, mg/100 ml SGOT, Karmen U BSP, % Calcium, mg/100 ml

Pre-therapy

With Therapy

Mean

Range

No.

Mean

Range

4.01

(1.97-7.85)

25

4.81

(1.92-17.6)

0.5 32 9

(0.3-0.8) (11-59) (7-12)

26 25 9

0.5 23 9

(0.i-i.0) (17-67) (3-22)

9.56

(9.34-9.90)

25

10.04

(8.90-13.3)

These tests included bromsulphthalein retention (BSP), bilirubin, glutamic-oxalacetic transaminase (SGOT), alkaline phosphatase (alk p'tase).

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In one patient, 1 and 2 months after treatment was instituted, the values of these liver function tests increased transiently, reverted to normal by 4 months, and remained normal for an additional 30-month treatment period.

Serum calcium was sporadically increased in another

patient, presumably reflecting progressive osseous metastatic disease. These transient abnormalities with mestranol treatment are represented in Table 3 by the values of the upper limits of the ranges of the determinations. Average values with treatment compared to pre-treatment determinations were changed in a variety of determinations.

Serum choles-

terol values increased 6%, triglyceride levels increased 40%, and phospholipid levels consistently increased by 20% (Table 4). Free TABLE 4 Some Tests of Metabolic and Endocrine Function during Mestranol Treatment Test

Cholesterol, mg/lO0ml Triglycerides, mg/100ml Phospholipids, mg/100ml Free fatty acids, ~Eq/L a-lipoprotein, % Blood sugar, mg/100ml PBI, ~g/10Oml TBG, ~g/10Oml HGH, m~g/10Oml Cortisol, ~g/100ml Insulin, ~U/100ml 17-Ketosteroids, mg/24hr 17-Ketogenics, mg/24hr Gonadotropins, arbitrary units

Pre-therapy

With therapy

Mean

Range

No.

Mean

Range

248

(187-301)

14

262

(209-353)

129

(84-232)

14

174

(95-297)

239

(139-300)

14

287* (193-402)

837 25 82 5.6 19.1 2.12 14 19

(686-1085) (16-29) (54-114) (3.3-7.8) (14.8-24.2) (0.28-5.1) (10-22) (17.5-21)

14 14 17 16 i0 14 14 2

632* (330-1268) 35* (22-52) 70* (35-100) 6.8 (3.1-9.6) 43.4*(26.4-65.4) 7.2 (1.6-17.0) 66* (25-114) 20 (15-25)

i0 6

(8-i0.7) (6)

i0 9

13 i0

(5.1-20.8) (3.3-20.8)

251

(101-644)

7

98*

(83-126)

*Means of all 4 patients on treatment changed in the same direction, compared to pre-treatment values.

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fatty acid levels, which were above normal before treatment, ly decreased to average values in the normal range. values consistently increased by 40%. less in all treated patients. treatment.)

consistent-

Alpha-lipoprotein

Blood sugar values were 15%

(Plasma insulin was unchanged with

Plasmal cortisol was increased greatly in all patients,

and plasma growth hormone (HGH) increased 3-fold.

Urinary gonado-

trophin excretion diminished in all patients.

There was a modest

increase in protein-bound iodine (PBI) values;

thyroxine-binding

globulin capacity (TBG) doubled.

Urinary ketosteroids were changed;

there was possible increase in ketogenic steroid excretion. DISCUSSION Data from toxicity studies in animals indicated possible changes in hemogram, (23).

liver and kidney chemistries with mestranol treatment

No serious drug toxicity was observed in the treated patients

studied.

The incidence of systemic "symptoms" observed with mestra-

nol, 3 mg daily, was minimal in contrast to the numerous complaints observed

in patients receiving other estrogens

(24).

The transient

reversing alteration in liver function tests observed with treatment in i patient, with no change in these parameters in the other patients, suggests that serious hepatotoxic effects reported with smaller doses of mestranol (25) represent idiosyncrasy rather than inherent cumulative hepatotoxicity of the drug. In the current study, mestranol was given alone (without progestational agents) without interruption, postmenopausal women.

in large dose (30-60 x usual), to

These conditions permit observation of maximum

individual drug effects with minimal modification by the patient's own ovarian function.

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Metabolic abnormalities characterizing untreated postmenopausal patients with metastatic breast cancer include:

increased basal

levels of circulating free fatty acids, impaired oral and intravenous glucose tolerance with delayed prolonged insulin secretion and hyperresponsiveness to insulin of free fatty acids (antilipolytic effect), sluggish free fatty acid response to parenteral growth hormone administration. The alterations in tests of endocrine and metabolic function observed in mestranol-treated women with breast cancer are similar to those observed with administration of estrogens to healthy women. (i, 27, and 28).

These effects include:

enhanced peripheral utiliza-

tion of glucose, decreased insulin sensitivity (insulin resistance), hyperresponse of insulin to glucose administration, increased secretion of growth hormone, increased oxidation of cholesterol, decrease in plasma cholesterol and low-density lipoprotein, increase in triglyceride-rich very low density lipoprotein and increased plasma triglycerides, increased plasma phospholipids, increase in high-density lipoprotein, decrease in post-heparin lipolytic activity.

Such effects

may be mediated through hypercortisolism or an effect on the liver; the underlying mechanisms are unknown.

Increase in circulating thyroid

hormones and binding-proteins also occurs. Additional responses to mestranol observed in the present study include:

a fall in fasting blood sugar (described in obese woman), de-

crease in basal free fatty acids (perhaps secondary to amelioration of breast cancer).

Similar results have been observed in 16 postmeno-

pausal women with metastatic breast cancer given diethylstilbestrol, 15 mg daily (29).

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ACKNOWLEDGMENTS Mestranol (NSC-84032) was provided by the Endocrine Evaluation Branch of the National Cancer Institute in i mg tablets from a single lot. This investigation was supported in part by U.S. Public Health Service Research Grant CA-3358 from the National Cancer Institute and AM-3655 from the Institute of Arthritis and Metabolic Diseases.

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