BY: ALFRED A. LOESER, M.D.

Female and male hormones in tablet form can be implanted 

subcutaneously, and in this way accurately controlled

use of the hormones over long periods is obtained

(Deanesly and Parkes, 1938; Parkes, 1938). In human

beings this method has not yet been extensively tried

(Bishop, 1938; Foss, 1939; Geist, Salmon, and Walter,

1939).

Below are given reports of twelve patients who were

given in all sixteen implantations of hormone tablets.

Female hormone was implanted in the case of two patients

and male hormone in the case of the remaining ten.

Implantation of Tablets of Oestradiol

Both of the women whose cases are here recorded had

hitherto been sterile; in both the uterus was infantile;

both desired children and had on many occasions been

treated unsuccessfully with female hormones and anterior

lobe preparations.

Case 1.-The result of the implantation was negative, as

the tablets were expelled again ten days after insertion. This

woman was very thin and had a scanty subcutaneous layer of

fat; the tablets had been implanted too near the skin.

Case 2.-The patient is 32 years of age; she did not

conceive either with her first husband or with her present one.

Mud-bath and diathermic treatment and dilatations and

curettage of the uterus were of no avail. Tubes were open.

Menstruation was regular. Uterus was very firm; measurement

with a probe gave barely two inches. After injections

of almost one million units of oestrogenic preparation during

six months the uterus became softer in consistency and its

size aiso seemed to increase, but it reverted to its old firm

consistency immediately the treatment was left off. In order

to apply continuous stimulation to the uterus, five tablets of

oestradiol were implanted deep in the subcutaneous fat of

the right hypogastric region on September 6, 1938. (Each

tablet weighed 15 mg.) The last normal menstruation

occurred on September 14, and then, as expected, menstruation

ceased. On January 1, 1939, the periods returned, and in

February and March there were haemorrhages lasting up to

three weeks. In April they increased still more, as had been

previously expected. Curetting revealed a uterus more than

three inches in length and a definite cystically proliferated

mucous membrane. The Aschheim-Zondek reaction was

negative. On May 13 that is, 249 days after the implantation

-the tablets were removed by means of a small skin incision,

and the amount of hormone absorbed was determined. Then

menstruation was again normal, the last period being on

October 4, 1939, when the uterus was the same size as during

the curetting. In November signs of pregnancy were observed,

and on the 10th of that month the Aschheim-Zondek reaction

was positive.

In March, 1940, the uterus corresponded in size to that of

a fifth-month pregnancy; the Aschheim-Zondek reaction was

again positive. The pregnancy so greatly desired by the patient

has undoubtedly been attained, so far without complications.

Implantation of Testosterone Tablets

Five women with fibroids of the uterus complicated by

menorrhagia were treated; one woman with functional

bleeding; two patients with chronically recurring mastitis

and multiple nodules in the breast; and, finally, two with

cancer of the breast, one of whom, after numerous operations

and x-ray treatment, was to be regarded as hopeless,

while the other, after a radical operation and frequent

x-ray treatment, had continual recurrences.

Case 3.-The patient, 42 years of age and childless, had

previously had a laparotomy on account of an ovarian cyst,

now a cervical fibroid larger than a fist, of intraligamentary

development. Menstruation lasted up to fourteen days, with

much flow of blood. In 1937 and 1938 1 gave her injections

with testosterone propionate and inunctions into the skin of

an alcoholic solution of the same hormone. Results were

good, but only temporary. On September 12, 1938, twelve

tablets of testosterone propionate, amounting altogether to

600 mg., were implanted. From September 2 to 16 occurred the

last profuse menstruation ; on the 24th there was a haemorrhage

lasting five days: and then there was amenorrhoea

until February 20, 1939. After that there were apparently

two very short periods, and from April to July there was

amenorrhoea. In July there was a haemorrhage lasting six

days, followed by complete amenorrhoea until the present

time, without the appearance of menopausal symptoms. The

fibrpid has not changed its size or consistency. The patient,

who had refused operation, is well satisfied with her present

condition. Time of observation after the implantation

amounts to sixteen months.

Case 4.-Patient 29 years of age. In April, 1937, I

enucleated three intramural fibroids from the retroflexed

uterus. Nevertheless menstruation remained as severe as

previously and lasted over a week; severe, at times intolerable,

premenstrual breast pains persisted. On August

19, 1938, two tablets of testosterone propionate (in all 948 mg.)

were implanted. Amenorrhoea followed. The first period

was on November 22. On November 28-that is, 101

days after the implantation the two tablets were expelled

as a result of a severe traumatic haematoma of the abdominal

wall. During the first year after the implantation periods

were normal, and there was hardly any complaint of premenstrual

breast pains. The condition of the generative

organs was normal. From October, 1939, onwards that is,

fifteen months after the implantation-the periods once again

became menorrhagic. Time of observation was eighteen

months.

Case 5.-The patient, 43 years of age, with a submucouLs

fibroid the size of a fist, had periods lasting ten days with

much loss of blood. Operation was refused. On October 15,

1938, twelve tablets of testosterone (each tablet containing

50 mg.) were implanted. On October 24 a haemorrhage

lasted ten days; after that there was amenorrhoea until

January 28. 1939. Regular periods of five days' duration

followed, the fibroid being unchanged. Last examination was

in July, 1939. Time of observation lasted nine months.

Case 6.- The patient, 40 years of age, had been previously

curetted and treated by x rays in Vienna for menorrhagia.

For some months past the periods had again been very severe,

lasting fourteen days. There were a few hard fibroids in a

uterus almost the size of a fist. Operation was refused, On

February 1, 1939, twelve tablets of testosterone (in all 600 mg.)

were implanted. There was amenorrhoea until June 5, 1939,

and after that normal five-day menstruation. Final examination

in the middle of January, 1940, revealed the fibroids the

same size as previously. Periods were normal, lasting five

to six days, and there was far less loss of blood than hitherto.

Time of observation after the implantation-nearly one year.

Case 7.-Patient 34 years of age. There was definite

masculine distribution of hair on the legs and abdomen.

Previously removal of an ovarian cyst and a fibroid had been

performed. The menorrhagia then disappeared for one year

only. Intolerable breast pains occurred one week before each

menstruation. For some months past the menorrhagia had

recurred. A small fibroid the size of a walnut could be felt

in the uterus. On May 13 386 mg. (eight tablets) of testosterone

were implanted. The breast pains disappeared

entirely but the menorrhagia was not affected ; in fact, the

impression is that the periods became still more severe. On

August 22 the uterus was curetted and the endometrium was

found to be atrophic. On the same day the implanted tablets

were removed; only three were found, and they were much

thinner and greatly reduced in size. During the next four

months the premenstrual breast pains disappeared, but the

menorrhagia had diminished by two days only, though the

loss of blood was still considerable.

Case 8.-The patient, 38 years of age, had so severe a

menorrhagia in consequence of a fibroid that she was unable

to work. On December 29, 1939, 600 mg. of testosterone

propionate were implanted. On the sixth day after this we

tried to detect the tablets in the tissue by x rays. The tablets

could not be detected with certainty, although it was thought

that some crystal-like shadows could be observed. The period

of observation is too short for account to be taken of the case

here.

Case 9.-The patient was 40 years of age, with regular

menstruation. Her mother had died of cancer of the breast.

For the last five months she had had pains in the breast and

a nodule the size of a bean could be felt in the right breast.

Histological examination revealed chronic mastitis. The

patient had had the same symptoms a year ago. On March

27, 1939, 300 mg. of testosterone were implanted. Ten days

later the breast pains disappeared. There was amenorrhoea

for six weeks, and after that the periods were normal again.

The whole of the remaining tumour had disappeared. In July,

1939, however, it was again possible to feel a small nodule

in another part of the right breast; but it had vanished in

three weeks. So far no new tumour has appeared; there are

no more pains. Time of observation after the implantation

was ten months.

Case 10.-The patient was 40 years old and her menstruation

was normal. During the last six years she had been

operated on four times on both breasts for cystic tumours.

Histological examination revealed a fibro-adenoma. For three

months before implantation she had noticed a tumour in the

right breast. It was the size of a walnut and gave rise to

-considerable pain. On September 9, 1939. 700 mg. of testosterone

(fourteen tablets) were implanted. Amenorrhoea

followed and has persisted till now (February 2.O, 1940).

Examination carried out six months after the implantation

shows that nearly the whole of the tumour has disappeared;

there is no pain. (Another very remarkable coincidence is

that the patient stated she was able to dispense with her

glasses, which she was wearing for myopia. The same

observation was made in another case in which 600 mg. of

testosterone propionate were injected.)

Case 11.-The patient was 60 years of age, and had been

treated for the last eight years with radium for carcinoma

of the breast. Multiple recurrences were treated by operation.

Metastasis now exists on both sides, supraclavicular and

mediastinal. In the right axilla there is a diffuse infiltration;

around the right nipple there is a suppurating ulcer the size

of a half-crown. The radiologist called in recommended

morphine for combating pain; on account of the disseminated

carcinosis no other treatment was carried out. On July 1,

July 14, and October 3, 1939. 1,650 mg. of testosterone

propionate in all were implanted. On October 3 two of the

tablets implanted on July 14 were removed in order to determine

the degree of absorption. The temporary result was a

superficial swelling around the right nipple, accompanied by

considerable reduction of the ulcer, a softening of the hard

infiltrations in the armpit, and also a superficial swelling and

pigmentation of the healthy breast. Striking features were an

increase in weight by 5 lb. and an obvious state of improved

health; the patient also had a certain dark pigmentation of the

face as if she had been given ultra-violet rays, and the pain

along the right arm was considerably less. This improvement

lasted only until the middle of November, when the patient's

weight again fell off, and further decline could not be checked.

Case 12.-The patient was a woman 45 years of age, who

after radical operation for cancer of the breast on the right

side and much x-ray treatment over a period of one year

showed two recurrences in the operation cicatrix. There is

now a fresh acute recurrence in the armpit. On August 22,

September 18, and November 8, 1939, 1,500 mg. in all of

testosterone were implanted. In the beginning the patient

showed similar symptoms to those described in the case of the

preceding patient, but up to January, 1940, no change in the

size or consistency of the recurring tumour in the axilla could

be found (although it did not reveal any growth), for which

reason the patient was again given x-ray treatment.

Technique of Implantation and Absorptive Powers

of the Tissues

Under a local anaesthetic an incision two to three

inches in length is made through the skin of the right or

left hypogastric region ; the fatty tissue is drawn apart,

and each tablet (which has been previously sterilized in

boiling water for three to five minutes) is embedded

separately in the subcutaneous tissue. The tablets should

not be in contact with one another and should not lie

directly beneath the skin, as otherwise they act too much

as foreign bodies and are expelled again too easily. The

deeper the tablet lies the better it will be retained; the

larger the tablet the less certain the chances of healing

up. A tablet one-third of an inch in diameter is most

suitable for implantation, although the absorption proceeds

more rapidly when the surface is larger. The skin,

and on occasion the fatty tissue (when there is a thick

layer of the latter), is closed with a few stitches of catgut.

This technique has given me the best results.

In Cases 2, 4, 7, and 11 it was possible to ascertain the

loss in weight undergone by the implanted tablets during

their retention in the body. When the tablets were removed

it was found that some were still lying free in the

fatty tissue, some were attached to the fatty tissue by

light fibrous bands, and one tablet was surrounded by a

tough fibrous layer. It will be seen from this that the

absorption need not proceed uniformly when the implanted

tablets are not lying quite free.

In Case 2 five tablets of oestradiol had been implanted,

each tablet weighing 15 mg. On removal they weighed

3.8 mg., 5 mg., 2.8 mg., 6.4 mg., and 6.5 mg. respectively.

Within 249 days, therefore, there had been a total absorption

of 50.5 mg. of oestradiol. In Case 4 there had been,

within 101 days, an absorption of 376 mg. of testosterone

propionate out of the 948 mg. implanted; in Case 7

(likewise in a period of 101 days) 368 mg. of testosterone

out of a total of 386 mg. had been lost. In Case 11 (of

carcinoma), finally, within a period of eighty-one days,

34.5 mg. had been absorbed from one of the two tablets

(each of which had weighed 48 mg.) and 34 mg. from the

other. At the beginning, when the tablet presents a large

surface, more is absorbed than later on, when the surface

of the tablet has already been considerably reduced in size.

Results of Oestradiol Implantation

As regards Case 2, in which the female hormone was

implanted, the patient reacted in the same way as the

experimental animal. The large quantity of oestradiol

depressed the function of the anterior lobe of the pituitary

gland; gonadotrophic hormones were not emitted from

the anterior lobe. Consequently maturation of ovum and

menstruation did not occur. Just as in a normal pregnancy

the function of the anterior lobe of the pituitary

gland is depressed by the oestrogenic substances produced

in the placenta, and the ovary forced into a kind of

hibernation, so in this case the same effect was produced

by the implant. Nevertheless local action of oestradiol

on the uterine muscle and mucous membrane of the uterus

became plainly visible. The uterus grew, and the mucous

membrane became converted into cystically proliferated

endometrium and was cast off gradually by haemorrhages.

After removal of the hormone tablets the anterior lobe

gradually recovered, the hibernating ovary was stimulated

by fresh gonadotrophic hormone produced in the anterior

lobe, ripening of the ovum occurred again, and hence

there was normal menstruation. The muscular apparatus

of the uterus had been substantially strengthened and was

now able to draw up the semen, which it had previously

been unable to do because of muscular deficiency. The

patient became pregnant.

Rationale of Male Hormone Therapy

French authors (Mocquot and Moricard, 1936; Capitain

and Desmarest, 1937; Turpault, 1937) were the first

to use the male hormone in gynaecological affections, but

only after the experimental investigations of Zuckermann

(1937) and my proof (1938) that a sufficiently large amount

of male hormone produces in women a temporary atrophy

of the endometrium (maintainable for a lengthy period)

and a temporary sterilization could a sure enough basis of

a quantitative character for therapy be established. Foss

(1938) in this country and, in particular, American

authors (Gaines, Geist, and Salmon, 1938) have later

confirmed this.

The endometrium is the mirror in which are reflected

the hormonal processes taking place in the ovaries. The

growth and the ripenipg of the follicle are reflected in this

mirror, as are the birth and the death of the corpus

luteum. In the same way the endometrium reflects all

the processes which occur after absorption of the implanted

artificial ovary and of the artificial testicle in tablet

form, although, of course, the artificial ovary is incomplete,

as is the artificial testicle, for each yields only a

single hormone. Both artificial glands, however, have a

common feature in that they depress the function of the

anterior lobe of the pituitary gland and reduce the secretion

of the gonadotrophic hormones, or even suppress it

entirely when the implantate is sufficiently large. In

Cases 3 and 5 the gonadotrophic hormones were examined

before and after the implantation (Dr. Wiesner), and in

the first case they disappeared entirely from the urine after

the implantation, while in the other case they were reduced

by one-half. If atrophy of the endometrium ensues, as in

the unsuccessfully treated Case 7, but bleeding nevertheless

persists, the amount of testosterone (less than 400 mg.)

may have been too small to depress the anterior lobe.

In fifty-five cases in which injections of testosterone propionate

have been given-reports on which will be

published later-an average of 700 mg. of testosterone propionate

had been necessary in cases of hyperfolliculinaemia

in order to obtain the desired results. It might

perhaps be suggested that this dosage, which might be

called "hormone atrophy dose" for the endometrium

(H.A.D.), should be designated as a basic value and only

a portion of it be given, depending on the case. It is

approximately twenty times the dose of follicular hormone

necessary to attain a normal proliferation of the

endometrium in cases of absent ovaries or of primary

amenorrhoea (35 mg. oestradiol benzoate). This might be

called the "hormone proliferation dose" for the endometrium

(H.P.D.) (1933, 1934). For antagonizing this

proliferation dose the atrophy dose of testosterone would

be necessary.

If pronounced hyperfolliculinaemia and hyperproliferation

exist this atrophy dose would have to be increased.

Even the largest doses of male hormone, such as were

injected in earlier attempts, do not act on the fibroids

themselves, which, according to our present-day concepts,

are considered to be the result of hyperfolliculinaemia.

In the case of one patient who had been treated with such

large doses by injection, and on whom I subsequently

performed a supravaginal amputation of the uterus, the

histological examination of the fibroid (performed by Dr.

Oliver) revealed no change.

In the five women with haemorrhages treatment was

successful in three, of only limited success in one-a

younger woman (Case 4) in whom after an accident the

tablets were expelled-and unsuccessful in one (Case 7),

in whom the amount of the implanted hormone was

too small. Improvement was obtained in the two women

with chronic mastitis. It is known, and has been established

particularly by French authors, that even small

doses when injected give good results in this conditiona

view also supported by workers in this country (Spence,

1939). But in this connexion it must be observed that

results are also to be obtained with follicular hormone and

other methods of treatment, such as diathermy. Treatment

with male hormone is based on the fact that excess

of follicular hormone produced in the body causes the

proliferative processes in the breast, and that this excess

cannot be antagonized for a long period by small doses

of male hormone, but only by really large ones.

Testosterone and Cancer

If it is assumed that excess of follicular hormone can

produce not only proliferative processes in the mammary

gland but perhaps even precancerous processes, treatment

with male hormone as an antagonist would be justified

in cases of cancer of the breast. Experimental investigations

with testosterone in mice with high incidence of

cancer of the breast are available (Lacassagne, 1937;

Flacks and Isser, 1938). Testosterone propionate acted in

a prophylactic manner. I have had under observation two

patients whose breasts were removed for cancer and who

suffered from recurrences at frequent intervals. The recurrences

had disappeared after irradiation when I saw

them. I treated them for menorrhagia with injections of

testosterone propionate, and up to date there has been no

further recurrence for two and a half years ; this suggests

that testosterone had an inhibiting effect (1939).

In my two cases of cancer (11 and 12) testosterone had

no effect on the growth itself.

General Effects of Testosterone Therapy

All patients who have been treated show throughout

the following general effects: (a) Enlargement of the

clitoris so long as the male hormone was acting. No

patient found this to be unpleasant. (b) Increased sexual

drive even in older women. The fact that this can be

found without a single exception, even when the male

hormone is given by injections in sufficient amounts, shows

that testosterone can be designated as an infallible aphrodisiac,

although of course only doses over 300 mg. have

effect. (c) Deepening of the voice without anatomic alteration

of the vocal cords. This disappears after three or

four months. (d) Temporary occurrence of lanugo on

the face, which also disappears again after some time.

As regards the psychic side of the patients treated in

this manner, they all acknowledge a great feeling of wellbeing,

more balanced moods, and clearer thinking; and

some profess also a greater determination. We might

therefore speak of a "chemistry of the emotions " in

order to express that the temperament is influenced by

the chemical substance so long as the hormone is active.

It would be interesting to go further into this side of

hormone therapy, and to study how the feelings might

be chemically controlled. Some of Freud's theses would

perhaps have to be modified. Such discussions, however,

would lead too far from the original theme.

Summary

1. Female and male hormone can be implanted in

tablet form in as large amounts as desired without injury.

2. Female hormone was implanted to allow a small

infantile uterus to develop and to make it ready for conception,

and this was done successfully.

3. Male hormone was implanted to control serious

menorrhagia caused by fibroids. Good results were obtained

in the case of women near the menopause.

4. Male hormone was unable to influence successfully

existing recurrences of carcinoma of the breast following

an operation or x-ray treatment. To what extent male

hormone can have a prophylactic action against such

recurrence is not yet determined.

5. The general effect of implants of male hormone on

women is discussed.

I am highly indebted to Dr. Macbeth of Organon Laboratories,

and Dr. Neuman of Schering Ltd. for supplying these

tablets.

REFERENCES

BisIop, P. M. F. 01938). British Medical Journal, 1, 939.

Capitain, Mme, and Desmarest, E. (1937). Presse ?nfd., 45, 777, 1109.

Deanesly, R., and Parkes, A. S. (1938). Lancet, 2, 606.

Flacks, J., and Isser, A. (1938). C. r. Soc. Riol., Paris, 128, 506.

Foss, G. L. (1938). Lancct, 1, 992.

- (1939). J. Obstet. Gys'aec. Brit. Emnp., 46, 271.

Gaines, J. A., Geist, S. H., and Salmon, U. J. (1938). Endocrinology, 23, 527.

Geist, S. H., Salmon, U. J., and Walter, R. 1. (1939). Science, 90, 162.

Lacassagne, A. (1937). C. r. Soc. Biol., Paris, 126. 385.

Loeser, A. A. (1933). Z. Geburtsh. Gynak., 104, 516.

(1934). Rev. franc. Gyn&c., 29, 788.

(1938). Lancet, 1, 373; Int. Congress of Gynaecology (Amsterdam), May.

(1939). C. r. Soc. franc. Gynec., Feb., 77.

Mocquot, P., and Moricard, R. (1936). Bull. Soc. Obstet. Gyn6ec., Paris, 25,

791.

Parkcs, A. S. (193,8). British Medical Jour-nal, 1, 371.

Spence. A. W. (1939). Lancet, 2, 820.

Turpault. M. (1937). C. r. Soc. franc. Gynec., October, 181.

Zuckermann, S. (1937). Lancet, 2, 676.