ACNE VULGARIS

A Study of One Thousand Cases

Jerome Kearney Fisher, M.D., Med. Sc. D.

            This study was set up to learn some of the possible influencing factors in acne vulgaris as are found in the adolescent.  The patients were only those which have been seen personally this past ten years by the author in his private practice and the study does not include the secondary involvement of the comedo by pyogenic organisms which produce pustules and scarring.  The cases in this report were taken consecutively from the files and not picked at random.  Detailed histories were taken on all cases at time of the initial visit.

            This paper involves 1088 cases of acne vulgaris.  Of these, 721 were females and 367 were males.  It is seen that a preponderance of twice as many females sought treatment for their acne as males.  However, this should not be interpreted to mean that only half as many young men develop acne vulgaris as young women.  Unless the eruption becomes conspicuously active in the male, he very likely will not seek medical aid.  This is probably due to the fact that he is not developed or matured to the same degree as the female of the same age.  Nor is he influenced so much by the social implications of his condition.

            As will be shown further on, the activity of the eruption was much more severe in the male than in the female in its development.  Also, medical treatment is sought at an earlier age in the female and the eruption, although milder in the female, does persist much longer than in the male.

            In the etiology of acne vulgaris one finds that many factors have been considered by numerous investigators.  These have included allergies to food ^{13, 14, 15, 18}, nutrition ^{6, 9, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26}, drugs ²⁷, water balance ^{20, 28, 29, 30, 31}, stress and emotions ^{7, 32, 33, 34}, hereditary tendencies ³⁵, infection ⁶², and various hormones of the pituitary ^{36, 37, 38, 39, 40}, the adrenals ^{20, 48, 49, 50, 51, 52, 32, 33}, and the gonads ^{8, 10, 20, 33, 41, 42, 43, 44, 45, 46, 47}.  A few of these factors are considered primary; the others are secondary or contributory.

            This presentation will be divided into three parts; first, a review of the many factors that have been found to influence acne in young people, second, a report of the analysis of my own cases and third, a discussion based on the findings under these two headings.

Part I

RESUMÉ OF THE LITERATURE

Incidence of Acne Lesions

            In studying the incidence of acne vulgaris in adolescence Bloch³ in 1931 found in his study of 2136 individuals that 96.6 per cent of girls at 17 years of age and 99.5 per cent of boys at 18 years of age were affected with acne.  Goldzieher⁸ in 1947 found an incidence of acne vulgaris in 67 per cent of his patients between the ages of 15 to 18 years of age.  Robinson⁶ reported in 1949 on 2083 patients with acne; of these 130 were 15 years of age or younger; 1583 were between 16 and 25 years old.  Then in 1958 Warshaw¹¹ reported in a study of 1981 boys and girls the incidence of acne in boys and girls 17 to 18 years of age; this was 44 per cent for the boys and 30 per cent for the girls.

Incidence in the Male

            Forbes¹² in 1946 gave a very comprehensive report of the incidence of acne in 2500 men in service from ages 18 to 49 years.  The accompanying table is taken from his paper.

Incidence in Men Ages 18 to 49

Ages                No. of Men     Comedones Only        Comedones with Papules or Pustules

18-19                     189                        51 (27%)                                             49%

20-24                     568                        147 (26%)                                           33%

25-29                     626                        141 (23%)                                           21%

30-39                     906                        142 (16%)                                           13%

40-49                     211                          15  (7%)                                              8%

Variations of Activity of Acne

            Henricksen and Ivy² in 1938 observed that the peak of activity of acne appeared earlier in girls than in boys but the most severe cases were in the latter.

            Goldzieher⁸ in 1947 has noted that acne does not subside in the female at maturity as it does in the male.  He explains this observation by stating that the skin of the female is more sensitive to androgens than the male.  Also he noted that acne in the male is a self-limiting disease because the sensitivity subsides at maturity.  Belisario⁷ in 1951 also pointed out that acne in women in contrast to its presence in men may continue throughout the reproductive period.

Age Limit of Eruption

            Bloch³ stated in 1931 that acne is seldom seen after 30 years of age.  In 1942 Lowenthal moved the age limit up to 40 years.  Then Stillians⁵ in 1947 found that 63 per cent of 174 women with tuberculosis between the ages of 27 and 50 years had acne lesions; 4 of 10 of his tuberculous patients between the ages of 51 and 60 years still had acne vulgaris.  Strauss and Kligman⁸⁷ report finding acne and sebaceous gland enlargement in many young females one or two years prior to menarche.

Location

            Lynch⁵³ in 1939 made a study of the location of the activity of acne vulgaris.  He found the face the most common site in a group of 277 boys and 219 girls.  The trunk was involved much more often among the boys than the girls, and the back much more than the chest.

Elements of the Eruption, the Sebaceous Glands

            The pilosebaceous apparatus is the fundamental unit in formation of lesions of acne vulgaris⁴².  If comedo is not present, a clinical diagnosis of acne vulgaris cannot be made⁹.  The red papular lesion of acne usually develops from the microscopic comedones of the pilosebaceous apparatus of the skin and rarely from the large comedones.  Lorincz⁹ in 1963 stated that there is evidence that the acne lesions evolve only in those pilosebaceous follicles which are in the resting phase (telogen) of the hair cycle.

            Rothman¹⁰ had pointed out earlier that natural juvenile acne has two main pathogenic factors:  one, sebaceous gland hypertrophy and two, excessive follicular keratinization at the orifice which occludes the pore and hinders the expulsion of sebum.  The sebaceous glands are relatively small in childhood and attain full bloom at puberty; this is believed to be the principal factor in juvenile acne vulgaris⁵⁸.

            Sebaceous glands are holocrine and are usually multiple acinar glands⁴⁴.  They are most numerous on the scalp, forehead, face and chin, with fewer on the back and chest.  The hair follicle and sebaceous gland are invaginations of the surface epithelium.  The cells of the sebaceous gland become specialized so that the cells of the gland undergo fatty alterations; they throw off these altered cells and debris in the form of sebum⁴² into the cavity of the cystic sebaceous gland and its duct leading to the surface.

            Removal of the pituitary gland in rats results in the reduction in the size of the sebaceous glands; this is only partially counteracted by progesterone and testosterone therapy.  The pituitary then is itself necessary for the proper maintenance of sebaceous glands⁵⁸.  Lorincz⁵⁹ in 1963 confirms this observation by stating that among these hormonal factors, clinical experience and animal experiments indicate that androgenic steroids or progesterone in the presence of pituitary sebotrophic factor are the key endocrine stimuli which promote sebaceous glandular activity.

            At puberty an increase in sebaceous gland volume occurs with enlargement of lobules and possible formation of new lobules.  The pubertal stimulus acts by promoting mitotic division of the basal cells in the sebaceous glands.  No further growth of the sebaceous glands takes place shortly after puberty; an equilibrium is established even though the endocrine stimulus persists.  The maintenance of the sebaceous glands is under endocrine influence⁶⁰. 

            The role of testicular hormones in the male as affecting the sebaceous glands has long been recognized mainly on the basis of three observations:

1.      Prepubertal castrates and eunuchoid males do not develop seborrhea or acne, a disease which is invariably connected with sebaceous gland hypertrophy.

2.      Castrate and eunuchoid males develop acne if they are treated with testosterone.

3.      Normal males and females may develop acne if they are treated with large doses of testosterone⁶⁰.

Haskin, Lasher, and Rothman⁶¹ in 1953 proved that 10 mg. of progesterone given daily for 15 days in the white rat produced a 360 per cent increase in the size of its sebaceous glands.  A dose of 1 mg. daily of testosterone to white rats for 30 days produced a 500 per cent increase in the animals' sebaceous glands.

            From the available data one may conclude that pubertal development of sebaceous glands is an effect of testicular hormone in the male and of progesterone in the female.  Both exert a proliferative stimulus on the matrix of the cells of these glands.  There is no increase in the number of glands and the size of the single cells does not change in this hyperplasia.  However, the alveoli of the glands enlarge greatly⁵⁵.  This experiment has given rise to the hypothesis that in the human female adolescent acne is incited by the progesterone of the corpus luteum and not by the previously implicated adrenal androgens⁵⁸.

            English and Witkowski⁶² in 1964 have shown that androgens applied to the skin of eunuchs will cause sebaceous gland enlargement.  When the topical androgens are withdrawn from the eunuchs and prepubertal children, the sebaceous gland gradually returns to its original size.

            Rony and Zakon⁶³ in 1943 gave 6 prepubertal boys injections of testosterone proprionate for two weeks.  When biopsies taken from the pubic area 2 to 3 days after therapy were compared with those taken 2 to 3 days before the injection, a decided increase in both size and number of sebaceous glands was noted in all cases.

            Ebner³⁰ in 1956 commented that since the frequency of acne is in adolescence and worse during menstruation that a hormonal influence must be present.

            Pochi, Strauss and Mescon⁶⁷ in 1963 proposed further that two steroids are required at the same time to produce acne.  Dehydro-epiandrosterone is the adrenal steroid hormone most active in stimulating sebaceous gland activity while glucocorticoids act in a permissive capacity with physiologic amounts being necessary for sebaceous gland response to androgens.

Formation of Sebum

            Montagna⁴⁴ states that the sebaceous glands of man (and no other animal) in the fetal stage contains glycogen; however it disappears at 6 months of fetal life.  In cells undergoing sebaceous transformation, glycogen decreases at the same rate that lipid increases.  The distribution of glycogen is precisely correlated with lipid storage and it is likely that sebaceous transformation takes place by a conversion of carbohydrates to lipids rather than by an accumulation of fat from the blood.  Contarow and Trumper³⁸ are of the same opinion and explain that neutral fat which is ingested is taken up by adipose tissue while the fats forming sebum are synthesized in situ from carbohydrates and protein in the holocrine glandular cells.

            Whatever fat that is rapidly mobilized or stored seems to be through glycogen phase; this similarity of the sebaceous glands to adipose tissue, and particularly to brown fat makes possible the suggestion that the sebaceous lipids may be synthesized in part by local oxidative breakdown of glycogen.  The presence of glycogen in the fat of animals which have been starved and then fed a high carbohydrate diet is known.  In the normal rat, fat cells are ordinarily devoid of stainable glycogen; but after the injection of a single large dose of insulin, glycogen is present in large amounts in both the brown and the white fat.  The fat of diabetic animals contains no glycogen⁴⁴.

            Nicholas (quoted by Montagna⁵⁴) believes in the beginning of sebaceous differentiation that lipid droplets appear first within the mitochondria filaments of the individual sebaceous gland cells.  As the lipid droplets become larger and coalesce, the accompanying mitochondria are said to decrease in number.  Mitochondria seem to play a direct role in the synthesis of the sebaceous lipids; they are not transformed into lipids.  This lipid accumulation and fragmentation characterizes the end point of sebaceous cells⁵⁴.

            Histologic evidence strongly suggests that sebum lipids are built from protoplasm of the sebaceous glands basal cells.  Constituents of sebum probably are built from small carbon fragments which are formed in catabolic processes by the cells⁵⁵ and not excreted as lipids extracted from the blood.  Sebum is composed of glycerides and large amounts of esters of fatty acids with higher alcohols such as cholesterol²⁰.  Normal human sebaceous glands contain no free cholesterol, but the stagnant sebum of comedones and of early acne cysts contain an abundance of it⁵⁷.

            Montagna⁵⁴ in 1956 reported that treatment with estrogen increases the mitotic activity but the sebaceous glands become smaller.  Andrews⁴⁹ stated in 1965 that estrogens are capable of decreasing sebum production.

            Sebum is different from tissue fats in being composed partly or entirely of waxes.  Thus a number of unusual substances not found elsewhere in the body must be synthesized within the sebaceous glands.  The composition of sebum differs from species to species; cholesterol and large amounts of free fatty acids are perhaps the only substances which occur constantly⁴⁴.

            The origin of free fatty acid in surface lipids might be explained in terms of lipases which are known to be present in the sebaceous glands and the epidermis⁴⁴.

            The sebum of man contains squalene; its origin and function are unknown⁴⁴.  It is related to wool fat of sheep in that squalene chemically is an acyclic tri-terpene while wool fat is a cyclic tri-terpene.

            Vitamin D. may be formed in the sebum⁴⁴.

            Sweating seems to be a prime factor in the spread of sebum over the body⁴⁴.

Infection

            The Gram positive anaerobic diphtheroid bacillus produces proprionic acid from sebum⁶².  This bacterium has been termed Proprionbacterium Cornybacterium acnes, or acne bacillus.

            The secondary invader of staphylococcus with its coagulan positive actions is the organism that follows so many times after the appearance of the red acne papule to infect the comedo and do so much destruction and scarring.  This condition comes late in the formation of the severe red, pustular and scarring eruption.  Many factors such as susceptibility to infection, hygiene, local trauma, resistance to infection, and the number of initial papular comedones that have developed play a large role in the activity of this infection.

            The usual sequence of events is:  (1)  the sebaceous gland duct becomes plugged with sebum or detritus which hardens, (2) the local tissues try to remove this newly formed foreign body in situ by an inflammatory process, and (3) this draws blood to the site and plasma and lymph fluid leak out into the sebaceous gland structure.  And finally since this is open to the skin surface by way of the sebaceous gland duct, the whole pilosebaceous apparatus then is a culture for surface bacteria with culture medium in the form of serum present in the inflamed tissue.

Androgens

            Since Hamilton's²⁰ paper in 1941, the study of androgens as a direct and primary cause of acne has received a growing impetus as a factor in the etiology of acne vulgaris.  He pointed out that eunuchoids are individuals who do not mature sexually and never have acne.  Androgen is a secretagogue for the pilosebaceous apparatus and in the eunuchoid treatment with testosterone must be continued for three or six weeks before acne will appear.  Estrogens are low in patients with acne but eunuchoids have a lower level of estrogens than the individual with acne.  Rothman¹⁰ demonstrated in 1954 that the sebaceous glands in rats atrophy after castration and regenerate again on implantation of testicular tissue or on the administration of male hormone.

            The female, like the eunuchoid, is also able to respond to testosterone with the formation of comedones and papules²⁰.  It is at the time of sexual maturity that urinary levels of androgens become elevated²⁰.  Androgens can suppress both the production and some of the actions of estrogens.  Hamilton concludes further that androgens increase vascularization, cause cutaneous pigmentation, hold salt and water in the tissues and produce stimulation of sebaceous secretion.  Testosterone is conjugated in the liver to androsterone  before being excreted by the urine and is then biologically inactive⁴³.

            In 1963 Hamilton and Mester⁶⁴ found no acne in 91 eunuchoids nor in 11 oophorectomized females during age of adolescence; the eruption present at time of castration persisted for several months after operation.

            Hooker et al⁴¹ in 1943 demonstrated that the skin of estrogen treated rats became thin and the sebaceous glands were much reduced in size; however animals that received both estrogen and androgen were completely protected against these changes and the sebaceous glands were even more numerous and larger than in the untreated animals.  Goldzieher⁸ in 1947 next showed that the skin of the female is more sensitive to androgens than that of the male.  Also the female skin holds this sensitivity until later in life than the male.

            Sulzberger and Witten⁴² in 1951 stated that it was generally held that it is the ratio of circulating androgens to estrogens which is important as related to acne vulgaris rather than alterations of one or the other components alone.

            The observation of Palitz⁴⁷ et al in 1964 that acne is more severe and more prevalent in males than in females advances a possible theory in favor of androgens as a cause.

Sources of Androgens

            In the male the interstitial cells of Leydig of the testes secrete testosterone by stimulation from the luteinizing hormone of the anterior pituitary.  It is believed by some that about 2/3 of the androgenic substance in the urine of the male originates in the adrenal cortex⁴³.  But this hypothesis does not seem to hold in the case of the eunuchoid whose adrenals may be intact.  Androgens are present in the urine of females up to three-fourths of that of males.  The adrenal cortex has been thought by some^{43, 49} in 1955 to be the source of all circulating androgenic hormone in the female.  But Palitz et al⁴⁷ in 1964 state that both adrenal glands and the corpus luteum are sources of androgens in the female; progesterone is secreted by the corpus luteum during the luteinizing stage of the menstrual cycle.  The corpus luteum is the counter-part of the cells of Leydig in the male.  Polycystic ovaries have been shown in 1964 to synthesize more androgen than normal ovaries.  Virilism is associated with ovarian tumors which contain lutein tissue (producing progesterone); thus there is good evidence to believe that luteinized ovarian cells are potential sources of androgen⁸.

            Lorincz⁹ in 1963 feels that there is clearly an individual susceptibility factor to acne and this tends to be familial.  The individual susceptibility is well illustrated when adults are given large doses of androgens; severe acne tends to develop only in those who earlier in life had pronounced acne.

Pituitary Stimulation

            Cushing⁷⁰ in 1912 wrote that in hyper-pituitarism the skin is thick and coarse with enlargement and increased activity of the skin glands.  Semon and Herrmann⁶⁶ stated in 1940 their belief that pituitary basophilism is the primary cause of acne.  While Cohen³⁷ stated the following year that oily skin and comedones occur in acromegaly and gigantism, a disturbance of the acidophilic cells of the pituitary.  He further quotes Desaux in saying that seborrhea occurs in pituitary acidophilic activity.  Here we have two opposing views expressed twenty-five years ago.

            More recently, Butterworth and Chamberlain³⁹ in 1957 found that acne lesions are suppressed after pituitary irradiation.  The three gonadotrophic hormones affected in the pituitary secretion are:

1. The follicle stimulating hormone which causes the development of the follicles in the ovaries.  In the male it stimulates the testes with development of the semeniferous tubules and spermatogenesis.
2. Luteinizing or interstitial cell stimulating hormone which promotes secretion of progesterone in the female.  In the male it stimulates the interstitial testicular tissues to secrete testosterone.
3. Luteotrophic hormone (prolactin or lactogenic hormone) which in conjunction with estrogen stimulates proliferation of the mammary gland.  This latter hormone also initiates milk secretion in the mammary gland post partum⁷¹.

Chorionic gonadotrophin is produced in the placenta but differs from the pituitary gonadotrophin.  It is almost entirely gone from the blood and urine one week after delivery⁴³.

            Pituitary growth hormone is elaborated by the acidophilic cells of the anterior pituitary lobe.  The basophilic cells also present in the anterior lobe produce follicle stimulating, luteinizing, thyrotrophic and adreno-corticotrophic hormones.  Pituitary growth hormone acts directly on body structures as an anabolic hormone that promotes growth.  Warshaw⁶⁹ suggests that this hormone may have some relation to the postulated pituitary hormone "sebotrophin" of Rothman.  Since estrogens at puberty cause maturation and oppose the effect of the pituitary growth hormone, a low estrogen titer allows free play of pituitary growth hormone.  Thyroxin increases the secretion of the pituitary growth hormone.⁶⁸  Progesterone, according to Goldzieher in 1964, does not suppress human urinary gonadotrophin excretion; progesterone apparently acts directly on the ovaries to suppress follicle formation.

            The pituitary follicle stimulating hormone and the luteinizing hormone are suppressed by the feed-back mechanism of the estrogen⁷⁵.

Adrenals

            The adrenal glands have been associated with the formation of acne lesions because of the androgenic effects of some of their hormones.  The adrenal cortex secretes estrogen, progesterone, adrenosterone, dehydro-iso-androsterone and aldosterone (the salt retention hormone)^68.  Asel⁹³ in 1965 stated that dehydroepic-androsterone is secreted at the rate of 30 mg. a day by the adrenals; it may be the most important androgen secreted by the gland.  Dehydorepic-androsterone 100 mg. was given three times weekly to an adult male whose sebum had been previously suppressed by estrogen stimulated sebaceous activity.  Bruno Bloch³ in 1931 stated that it has long been recognized that in the female the adrenal cortical hormones are the important "androgenic" agents and must account for the growth of the pubic and axillary hairs, the stimulus of the pilosebaceous structures, the development of the apocrine glands as well as the concomitant appearance of acne.  Precocious development of adult characteristics of a masculine nature in a girl with adrenal cortical tumor may be accompanied by pronounced acne²⁰.  In adrenal virilism the urinary androgens were in level with normal women but their estrogens were low²⁰.  Hypertrichosis may develop in pregnancy and subside after childbirth or it may be associated with enlargement of the ovaries due to the lutein body cysts or extensive theca luteinization⁸.  Belisario⁷ observed that acne in the female with an adrenal tumor disappears after the removal of that tumor.  English and Witkowski⁴⁵ in 1954 stated that masculinizing tumors such as those which involve the ovaries, adrenals, pituitary and pineal glands can be responsible for acneform lesions?especially when all lesions are at the same stage.

            Androgenic turmore include the adreno-cortical syndrome, ovarian tumor, pineal tumor and testicular tumors³³.  Androgenic tumors in the adult female include Cushing's Disease, virilizing tumors and adrenal hyperplastia³³.  Sulzberger and Witten⁴² add such masculinizing conditions as menopause and arrhenoblastomas as having acnegenic effects.

            Haskin et al⁶¹ in 1953 reported that patients treated with adreno-corticotrophin developed acneform eruptions which were not identical with juvenile acne because they lacked the usual seborrhea and comedones.  Clinically and histologically in these eruptions the major component is excessive follicular keratinization; little if any evidence of sebaceous gland hyperfunction is present.

            Endogenous androgen production is a prerequisite to the development of steroid acne; therefore acne does not occur with oral steroids before puberty⁹⁵.  It is the author's belief that it is this corticoid stimulation of keratin in the follicles on the thighs and upper arms that is the cause of keratosis pilaris in young people.  No sebaceous activity is present in the lesion of keratosis pilaris either.  So that this eruption on the arms and legs may be a corticoid acne-like eruption.  But this will be the subject of another study.

Estrogen

            Nathanson et al⁷² first reported in 1939 that during catamenia the estrogens are low while the androgens do not fluctuate significantly.  In 1940 Lawrence and Werthessen⁷³ demonstrated a decrease from normal in urinary estrogen excretion by women with acne.  Wile at al⁷⁶ as early as 1939 demonstrated in acne patients an increase in urinary excretion of androgen and a moderate decrease in urinary excretion of estrogen in both sexes.  Lawrence and Werthessen⁵¹ in 1942 reported a decrease in the urinary estrogen excretion with a definite androgenic preponderance.  They concluded that comedones in acne were the result of an increase in the androgen-estrogen ratio.  Treatment with ethinyl estradiol or diethyl stilbestrol for 2 to 6 months cleared 15 of their 25 acne patients.

            Sulzberger and Witten⁴² in 1951 said it has been calculated that the estrogen blood level in normal menstruating women is at its highest plateau from about the 10^th to the 22^nd day post-menstrually.  The lowest level of estrogens is reached a few days before menses.  The exacerbation of acne tends to occur at precisely those times when the androgen-estrogen ratio tends to be highest.

            Estrogen is conjugated in the liver to glucuronides and sulfates of estriol, estrone and estradiol then excreted in the urine⁴³.  Estrogen as such is increased in the urine in liver disease if hepatic function is impaired as in cirrhosis or hepatitis⁴³; the increase is caused by diminished destruction or inactivation by the liver cells.  The excess estrogen then causes gynecomastia and menstrual disorders.  It caused testicular atrophy in males.  Malnutrition and vitamin B deficiency may interfere with hepatic inactivation causing premenstrual tension and cystic mastitis⁴³.

            Estrogen excretion is diminished in the male castrate indicating that a portion of the estrogen in the normal male urine is of testicular origin⁴³.

            Estrogen activity in girls' urines has been determined for as long as 18 months before menarche.  Boys and girls before the age of 11 years secrete about the same amount of estrogenic material in the urine⁷⁴.

            Greenblatt et al⁷⁵ in 1964 found the highest estrogen secretion in normal non-pregnant adult occurs around the time of ovulation; the lesser peak occurs about the 21^st day of the cycle. Estrogen secretion decreases rapidly in many, slowly in others.

            The Medical Letter⁷⁷ recently reported that estrogens can lower blood lipids.

Progesterone

            Progesterone, the hormone of the lutein body (granulosa lutein cells), is slightly androgenic.  It is secreted in significant amounts by the corpus luteum and by the placenta in the human⁷⁵.  It differs from testosterone chemically only in the short side-chain at the 17 position of the D-ring⁸⁸.  It is secreted by the corpus luteum and appears in the urine as pregnanediol the day after ovulation; it is also produced by the syncytial cells of the placenta and is formed in the adrenal cortex⁴³.  This androgenic effect is likely brought about by the conversion of progesterone into androsterone as reported by Dorfman and Hamilton in 1940.  Greene et al⁷⁸ have shown that when progesterone is given subcutaneously to castrated rats in the dosage of 2 mg. daily it is definitely androgenic; however it is less effective if given intraperitoneally.  Mason and Engstrom³² state that hydroxy-progesterone is androgenic.

            Sunderman and Boerner⁸⁰ have reported that progesterone increases in the blood level from the mid-period intermenstrually until the premenstrual phase when the amount decreases even to the point of completely disappearing 24 to 48 hours before the onset of menses.

            Culiner⁸¹ stated in 1945 that some of the active steroids seem to come from the ovary; evidence points towards the lutein body and luteinized theca or stroma cells as their most likely source of origin.  As a matter of fact, symptoms of masculinization such as facial hypertrichosis have been observed in cases in which the ovary was the site of extensive or pathological luteinization (progesterone origin).

            Forbes⁸² in 1950 reported that plasma level studies of progesterone showed that the progesterone did not disappear until after onset of menses.  Meltzer⁸³ in 1951 found that progesterone appears in the blood stream on the 14^th day of the menstrual cycle and reaches the highest level on the 22^nd day; then it gradually disappears at the end of the cycle.  The ovaries secrete 200 to 600 units more progesterone than estrogen⁷⁴.  The females have recurrent flares synchronous with the elevation of the progesterone level in the blood.  The ratio of the estrogen-androgen level changes to a relative androgenicity.

            Aron-Brunatiere⁸⁴ in 1953 noticed that acne is worse during the second half of the menstrual cycle and during the first few weeks of pregnancy?two stages characterized by progesterone secretion.  Because of the well recognized androgenic activity of progesterone, he suggested that in acne progesterone may be the factor in females analogous to testosterone in males.  He also noticed an aggravation of acne when he administered progesterone in doses of 20 to 30 mg. in 2 or 3 injections between the 21^st and the 25^th days of the menstrual cycle. 

           Haskin et al⁶¹ reported that 10 mg. of progesterone daily to rats gave the same sebaceous gland stimulus as was obtained with 1 mg. of testosterone.  Rothman¹⁰ stated that because of the powerful effect of progesterone as found by Haskin et al, it was hypothesized that pubertal development of sebaceous glands and occurrence of seborrhea and acne vulgaris in the female depend on the production of corpus luteum hormone in the same way they depend on the production of corpus luteum hormone in male.  This hypothesis, since it does not implicate the adrenals, is consistent with the observation that hypogenital males and females do not develop seborrhea or acne.  Smith⁸⁵ in 1959 found progesterone as effective as testosterone in stimulating the sebaceous glands of the elderly.  But Jarrett⁸⁶ also in 1959 gave progesterone in dosage of 25 mg. intramuscularly daily for 10-17 days in 3 males and produced no change in acne.

            Strauss and Kligman⁸⁷ in 1961 showed by their work that physiological amounts of progesterone given intramuscularly have been excluded as a source of stimulation to sebaceous glands.  Norlutin or acetate ester (a synthetic) in doses of 10 mg. will stimulate sebaceous glands where the smaller dose of 5 mg. is ineffective⁸⁸.  Human sebaceous glands can be directly stimulated by androgens even in the presence of large amounts of estrogens.  Pincus⁸⁹ on the contrary stated that endogenous produced progesterone exhibits strong androgenic properties whereas the synthetic progestational substance, norethynodrel, has been shown to have no androgenic properties.  However, he does not state his dosage.

Biologically, progesterone has been converted to testosterone in vitro by rat testicular tissue, by human ovarian tissue, and by human interstitial cell carcinoma tissue⁸⁸.

            Lorincz⁹⁰ in 1962 stated that the effect of progesterone is indirect on the sebaceous glands because female adult spayed rats showed increased sebaceous gland activity by volume of the glands.  Hypophysectomized spayed female rats had decreased sebaceous gland activity.

            Ebling⁹¹ in 1962 showed that estradiol when implanted for 280 days in normal and hypophysectomized or adrenalectomized female rats caused a significant reduction in sebaceous glands.  In castrated and in hypophysectomized castrated rats, testosterone promoted sebaceous gland cell proliferation and mitosis only in the presence of pituitary gland.  He also showed that the simultaneous administration of testosterone and estradiol produced a smaller gland than normal but one which had an increased number of mitotic cells.  Progesterone had no effect on sebaceous gland size, cellular proliferation or turnover time in intact or spayed mature or immature female rats.  Large doses of progesterone caused an increase in sebaceous gland size in castrated male rats.

            In agreement, Andrews⁹² in 1963 stated that progesterone is known to have androgenic properties in that it can maintain spermatogenesis in the hypophysectomized rat.

            Progesterone is rapidly metabolized in the body and therefore its administration should be every 8 to 12 hours⁷⁵.  Alkaline phosphatase activity is diminished by progesterone too⁷⁵.  Asel⁹³ in 1965 stated that progesterone in large doses may be converted to active androgen which will incite the acne process.  Therefore an increase in circulating androgens produced by the endogenous transformation of progesterone to an androgen could explain the exacerbation of acne during the luteal phase of the menstrual cycle⁴⁷.  If it were possible to eliminate the corpus luteum and thus the major source of progesterone, an important factor in the cause of acne in the female might be controlled⁴⁷.  Andrews⁴⁹ in 1965 explains the action of contraceptive tablets which suppress ovulation by the suppression of the secretion of gonadotrophin (folliculin) of the anterior pituitary with the contraceptive pills; no corpus luteum is formed because no follicule is formed in the ovary and subsequently no corpus luteum body develops and being absent, no progesterone is secreted.

            By the sudden withdrawal or decrease of progesterone and estrogen, menses appears.  In larger doses progesterone exerts androgenic effects perhaps by conversion to androgenic metabolites⁴³.  Strauss and Pochi⁹⁴ in 1964 point out that the prevention of ovulation per se does not appear to be related to any effect upon the sebaceous glands; if it were, the use of a progestin alone, i.e. norethyndrel would have been expected to cause more consistent decrease in sebaceous gland activity.

Stress and Emotions as Factors

            Stress and emotions are factors which are often difficult to prove as definite causes because they cannot be treated in a way so that they are applied or removed at will.  Stokes and Sternberg⁹⁶ in 1939 said that endocrine changes influence the skin in acne vulgaris through the emotions.  The reverse effect was shown by Mason and Engstrom³² in 1950 when psychotic men did not respond to a test of hot and cold stress with a rise in their 17-ketosteroid urinary excretion as did normal men.  Blackburn³³ in 1951 made the observation that androgens lay the fire for acne and emotions or other secondary factors light the fire.  Belisario⁷ in 1950 stated that psychosomatic relationship is unquestionably present in acne and that after the emotional conflicts are rationalized, the acne subsides.

            Larenz et al³⁴ in studying 30 patients in 1953 found a close relationship between life situations giving rise to a characteristic affective pattern and an increase in the acne pustule of these patients.  Stressful interviews with acne patients were associated with increased sebum secretion when "anger" was elicited and with decreased sebum secretion when the patient responded with "remorse."  Larenz then offers the thought that abrupt phasic alterations in activity of sebaceous glands may play an important part in comedo formation. 

Almost any type of stress or strain placed on the body tends to alter the function of the adrenals⁶⁸.  The regulation of secretion of adreno-corticotrophic hormone is of significant physiological and clinical importance⁷¹.  Augmented release of endogenous hormone is evident following any one of a wide variety of diverse and unrelated stimuli; they are trauma, emotional stress, drugs, chemical or bacterial toxic agents or substances normally present in the body, namely, insulin, thyroxine, vasopressin and epinephrine⁷¹.  The anatomical site of this mechanism appears to be the hypothalamus.  Experimental evidence suggests that this structure releases a humoral agent that reaches the adenohypophysis via the hypophyseal portal vessels.  The nature of this agent is as yet unknown but its stimulation of the pituitary results in release of ACTH⁷¹.  Harris et al as quoted by Williams⁶⁸ has shown that it is the portal blood circulation entering the hypophysis which carries the humoral substance and not through nerve impulses.  This was proved by section of the connecting nerve stock between the pituitary and the brain.  With acute or severe stress ACTH secretion may be increased within a few seconds⁶⁸.  However a lesion of certain centers of the hypophysis will prevent ACTH release following stress³⁸.

            The hypothalamic centers involved are activated through the cerebral cortex by specific stresses or psychic reactions⁶⁸.  The afferent impulses may arise in one of the organs of special sense or in the general sensory nerve endings.  Many of the effects of sensory stimuli on gonadal responses are well known.  For example, egg-laying of hens may be increased by prolonging the duration of exposure of the animal to light; red light being more effective than certain other colors.  Rabbits tend to ovulate only after coitus or with some other form of sexual stimulation.  The cycle of stimulus in the rabbit is as follows:  Genital stimulation?central nervous system?anterior pituitary?ovaries?uterine changes.  Suckling is associated with the following psychic changes:  Suckling?central nervous stimulation?pituitary?lactation.  At the time of adolescence the following stimulus cycle is found:  central nervous system?anterior pituitary?gonads?genitalia and body tissues.  The olfactory effects on gonadal stimulation are readily appreciated in the dog, bull and many other animals⁶⁸.  The effect of psychogenic influences on the endocrines can be illustrated by the responses to marked fear; there is an increased elaboration of epinephrine which increases the function of the pituitary, thyroid, adrenal cortex and pancreas⁶⁸.  Hypothalamic lesions have been known to be associated with decreased thyroid function but the main problem has been the mechanism by which the hypothalamus influences pituitary function⁶⁸.

            Lesions in certain portions of the hypothalamus can cause precocious or delayed puberty depending upon whether there is an increased or decreased stimulation of the pituitary gland.  Sebaceous gland hyperplasia develops in encephatitis lethargica.  Rothman¹⁰ has suggested that the encephatitis process may disturb the pituitary hormonal balance via nerve tracts leading to the pituitary.

            Goodman and Gilman¹¹⁴ state that caffeine excites the central nervous system at all levels.  Cocoa contains 50 mg. caffeine and theobromine per cup.  Cola nut used in the preparation of cola drinks gives about 35 to 50 mg. caffeine per bottle.  Children are more susceptible than adults to excitation by xanthines.

17 - Ketosteroids

            The term 17-ketosteroids refers to those steroids possessing a ketone group on the 17^th carbon atom.  They are all determined by the urinary excretion where they are excreted as esters.  Except for estrone which is removed at the time of urinary analysis, these steroids are termed urinary "androgens."  The chief 17-ketosteroid of normal and of abnormal urines is androsterne³⁸.  They are believed to represent the excretory transformation products of certain adrenal and testicular hormones.  The quantity excreted in the male serves as an index of the combined steroid secretory activity of the adrenal cortex and the testis and in the female chiefly of the adrenal cortex³⁸.  Normal men excrete more 17-ketesteroid than do normal women³². These compounds are discussed here principally as a means for possible study of patients with acne.

            Nathanson and Towney⁹⁹ in 1941 found increases in estrogens and 17-ketosteroids in urines of both sexes from the ages of 3 to 7 years.  From 8 to 11 years of age there was further increase but the 17-ketosteroids increased more rapidly in the female.  In prepubertal period 17-ketosteroids probably are derived almost entirely from adrenal cortex¹⁰².

            The close association of acne and masculinizing tumors and high androgen titers suggests that an excess of 17-ketosteroids is the determining factor in acnegenesis⁵¹.  Pincus¹⁰¹ found that 17-ketosteroids were depressed during sleep, whether by night or by day, and were elevated promptly after waking.

            Mason and Engstrom³² in 1950 found that orchectomy did not abolish excretion of 17-ketosteroids.  About one-third of 17-ketosteroids in normal male originate in the testes^{38, 69}.  They report that Kirschmann isolated the same quantity of urinary 17-ketosteroids from ovariectomized women as from the urine of normal women.  In women with Addison's disease, 17-ketosteroid almost entirely disappears from urine.  Hamblen observed decreases of 14 to 26 per cent in the excretion of 17-ketosteroid when estrogens were given to 22 women with various grades of ovarian failure who excreted moderately elevated amounts of 17-ketosteroid before treatment³².  McCullogh reports 5 eunuchoids excreted amounts of 17-ketosteroid which were about half the average of normal male³².  Callow, Callow and Emmens also found that the average 17-ketosteroid were less in eunuchoids than normal males³².  Mason and Engstrom³² found that total starvation for four days decreased the excretion of 17-ketosteroids 50 per cent in 3 normal men and one obese woman.  ACTH stimulates the increased excretion of 17-ketosteroids³².

            White and Lehman⁵² in 1952 treated 14 young men with diethyl stilbestrol and studied their 17-ketosteroid excretion; the average pretreatment 17-ketosteroids were 13.6 mg. per 24 hours; during treatment the average was 9.4 mg. with a drop of 4.2 mg. or 31 per cent per 24 hours.  But this was not correlated with clinical improvement!  In contrast English and Witkowski⁶² in 1954 showed that in individuals receiving estrogen sufficient to suppress sebum production the androgens, as measured by the urinary 17-ketosteroids, remained unchanged.

            Rothman¹⁰ has found it hard to accept the view that all of the 17-ketosteroids in the female originate in the adrenal cortex because male castrates and most ovarian deficient females have well functioning adrenal glands; yet they do not develop seborrhea or acne.

            Tomovitch et al¹⁰³ in 1963 found that infantile acne was not due to ketosteroids.  Patients have normal plasma corticoids.

            Andrews⁴⁹ states that 17-ketosteroids levels are normal in acne patients.  And Pochi and Strauss¹⁰⁴ mention that 17-ketosteroids are a poor index of androgenicity in that they are principally metabolites of adrenal cortical hormones which possess little androgenic potency.  Yet the adrenal secretions are considered the principal androgens by many others in both the male and female.

            It has been assumed that 17-ketosteroid determination is a measure of androgen production; an increased excretion of urinary 17-ketosteroids in acne would indicate androgen over-production and this accounts at least in part for the pathogenesis of acne¹⁰⁴.

            Henricksen and Ivy² in 1938 found that 46 per cent of girls in a children's home had flare-up of their acne lesions before or during their menses.  The acne eruption in 72 per cent of the girls in a university clinic were worse before or during menses.  Robinson⁶ found 111 exacerbations of acne before or during menses in his series.  Mason and Engstrom³² state that during normal menstrual cycles there is no evidence of cyclic variations in the excretion of 17-ketosteroids.  They believe the small fluctuations which occur bear no relation to the cycle.  Hamblen³² suggests that late or intercurrent ovarian failure for 6 months or more precipitates androgenic hyperfunction of the adrenal cortex.

            Blackburn³³ in 1951 stated that 17-ketosteroids include the excretion products of the androgens and parallel the activity of acne.  In view of the acnegenic effect of the androgens, the chemical relationship of the testicular ketosteroids and the adrenal steroids is a strong additional argument in favor of certain adrenocortical steroids being fundamentally involved in the production of acne in females and perhaps to some degree in males too⁴².  And since the exacerbation of acne tends to occur at precisely those times when the androgen-estrogen ratio tends to be highest, it is possible that androgens may be elevated at a time when estrogen is lowest.

            In most cases the urinary 17-ketosteroid outputs are a poor index of ovarian endocrine activity but since assays of testosterone are not readily available, they are the only available test⁶⁵.

Other Hormonal Observations in Acne

            Cohen³⁷ in 1941 noted that acne may disappear or become worse during pregnancy.  Andrews⁴⁹ in 1965 stated that acne is often worsened during the first few months of contraceptive therapy and this unfavorable result is probably due to the progesterone contained in the contraceptive; later the progesterone will have suppressed the pituitary so that no corpus luteum is formed.

            Acne eruptions are part of the adreno-genital syndrome and in neoplasm of the adrenal cortex, surgical removal clears the acne and masculinization⁸.  Treatment of both male and female patients with testosterone is likely to bring on acne⁸.

            In menopause the ovary becomes less responsive to pituitary gonadotrophic stimulation which causes an increased demand of follicle-stimulating variety³⁸.

Previous Laboratory Studies and Incidental Observations in Patients with Acne

            Knowles and Decker¹⁰⁵ in 1926 reported they found no difference in the titrations of gastric secretion of acne and non-acne patients.

            Leving and Kahn in 1922 and Greenbaum in 1931 reported separately that the glucose tolerance curve revealed no definite difference between individuals with or without acne.

            Wortes in 1937 gave 10 units of insulin to acne patients while fasting and allowed the patients to remain hypoglycemic; this cleared the acne.  Starvation decreases blood thyrotrophin along with other adenohypophyseal hormones except ACTH but its mode of action is not clear⁶⁸.

            Lynch⁵³ in 1939 found that girls with acne had lower basal metabolic rates than boys with acne.  Higher basal metabolic rates were reported for both sexes when the eruption was extensive.  Smith et al in 1951 found that 42.5 per cent of 353 acne patients had a basal metabolic rate less than a minus 10 while 2.3 per cent had a basal metabolic rate greater than plus ten.

            Stokes and King³⁵ in 1932 found the incidence of acne in parents of patients with acne is 26 times that of the parents of persons who have never had acne.  In a coverage with replies by mail, Ratzer found marriage brought about improvement in 43 per cent of 415 women; 53 per cent noted no change.  The largest percentage improved after the birth of a child¹⁰.

Nutrition

            Since the early studies in the cause of acne, nutrition has held a high place in discussion.  Buckley¹¹¹ in 1906 noted that bananas and nuts frequently aggravated acneiform eruptions.  Wells¹⁷ in 1932 cited cheese, eggs, pork and chocolate as factors in acne and White¹⁸ in 1933 found that chocolate, milk, wheat, oranges, tomatoes and nuts were the foods most frequently incriminated.  Sulzberger et al¹¹² in 1934 showed that patients with acne responded uniformly with an eruption when potassium iodide was ingested (This is a reaction seldom found in persons without acne diathesis.  Does this change unsaturated fats to saturated fats?).  Rowe¹³ in 1936 reported cure of acne patients with the elimination of certain foods.  Cormia¹⁴ in 1940 reported decided improvement in 30 patients treated strictly by a milk diet; also improvement occurred in several patients on a strictly milk diet in whom no evidence of food sensitivity could be determined.  (Does the combination of milk and other foods cause reaction?)  Cormia also found the foods producing the largest number of lesions were:  wheat, tomatoes, milk, chocolate, nuts and spinach.  Semon and Herrmann¹⁹ in 1940 found that a group of 11 patients with acne showed a lag in return of blood glucose tolerance curve after ingestion of 50 gm. of glucose; testing was done at half hour intervals.  When 3 to 5 units of protamine zinc insulin by hypodermic injection was given two to three times weekly improvement was noted; relapse occurred when the insulin was not given.

            Hamilton²⁰ in 1941 observed that no food stuffs seem to offer a common denominator in the induction of acne although exacerbations may be produced.

            Tobias²², Andrews²³, Sutton, Jr.²⁴, and White²¹ have all advised the elimination of milk in acne diet.

            Lutz²⁵ in 1944 believed that overloading the gastro-intestinal tract with carbohydrates (flour, potatoes, bread) was an important factor in the efflorescence of acne eruptions in 12 to 24 hours; nuts, cheese and sausage can cause this eruption in initially sensitive and persistent deep acne papules.

            Flood¹¹³ found from a study of previous papers and by clinical observations that foods commonly causing trouble are milk, pork, chocolate, tomatoes, oranges and nuts.

            Robinson⁶ reported in 1949 that the milk products, in his experience, were the most frequent cause of exacerbation with some patients drinking 2 to 3 quarts of milk a day; cola drinks and beer have also seemed to have aggravated the acne lesions.  In an acne case milk drinking may be a precipitating factor.

            Sutton, Jr.²⁴ in his 1949 edition believes the lipochrome pigments of tomato juice and orange juice, carrots, egg yolk and cod liver oil had as bad effect as butter fats.

            Andrews, Domonkos and Post²³ say the foods to avoid are chocolate, nuts, ice cream, egg yolk and cheese.

            Rothman¹⁰ reports Serrati as finding that an excessive fat and later carbohydrate intake produced an increase in liquid sebum in normal patients and in those with acne; 12 normal patients produced 15.4 mg. of liquid sebum over 40 sq. cm. of skin.  An excess of fat raised this to 21.0 mg. and when on carbohydrate it rose to 22 mg.  An acne patient on regular diet excreted 29 mg. of fat.  When fat was given, this same area produced 36 mg. and when on carbohydrate diet, 36.8 mg. were excreted.

            Rothman states further that forced feeding of animals with fats resulted in excretion of increased amounts of sebum.  The nutrient fat constituents were excreted unchanged?70-119% in two weeks.  In comparable overfeeding with carbohydrates, the increase was only 11-38 per cent.  Interestingly, when the abnormal type of feeding was continued there was a tendency for the amounting sebum to decline again.

            Kalz et al¹¹⁵ in 1951 found the average total serum lipids in 50 fasting patients with acne to be 690 mg. per cent while the averages for 10 normal patients was 616 mg. per cent.  The free serum cholesterol studies in the same 50 patients with acne averaged 81.92 mg. per cent while 10 normals averaged 68.8 mg. per cent.  However the lecithin averaged 264.3 mg. per cent for the patients with acne and 313 mg. per cent for the normal patients.  Some experiments suggest that extremely high fat or carbohydrate diets enhance sebum production¹⁰.

Water Balance in the Skin

            Stokes and Sternberg⁹⁶ in 1939 stated that increased water retention in the skin leads to infection.  Barber in 1948 also observed that fluid retention in the skin favored bacterial infection.

            Hamilton²⁰ said that sodium chloride and water retained by adrenal cortical substance, androgens, estrogens or luteal substances may make acne worse.  Progesterone favors the retention of sodium and water in the tissues³⁸.  Water retention also accompanies adrenal-cortical hyperfunction³⁰.  Patients with Addison's Disease rarely have acne or eczema according to Ebner³⁰.

            Aldosterone is the salt-retention hormone⁶⁸.  And an excess of this hormone (aldosterone) may lead to a hypertensive syndrome⁶⁸.

            Cohen³⁷ in 1941 felt that the position of water balance with regard to acne was obscure but that there was sufficient evidence to suggest that changes in the water metabolism may be of some importance in acne.

            Wirth¹¹⁷ in 1938 had 32 patients on a low salt diet which resulted in improvement in their acne in two years.

            Sodium and chloride are the extra-cellular electrolytes¹¹⁸.

            In absence of adrenal hormones the renal tubules (epithelial cells) appear to be unable to resorb Na (also Ca and K) adequately from the glomerular filtrate in spite of a low Na plasma³⁸.

            Williams⁶⁸ says that somatotrophin produces a retention of sodium, potassium and chloride but causes diuresis of water.

Milk Drinking as a Secondary Factor in Acne

            As has been mentioned previously in this paper, many dermatologists have observed that milk-drinking is a factor in causing activity of the eruption of acne.  Sutton¹²⁰ in 1956, in commenting on acneform eruption due to corticotrophin, said that it is interesting that there is another chemical, like androgen and progesterone, which stimulates sebaceous glands to hypertrophy and over activity.  He feels this hormone is present in the mammary secretion of the cow and is in skimmed milk as well as whole milk.  This endocrine substance, then, is effective in stimulating the sebaceous glands of the human being when it is ingested. 

            Examinations of milk as pointed out by Munch¹²¹ in 1954 show that estrogens are present in the milk of brown mountain cattle but no androgens were evident.  Estrogen levels are markedly increased in the pregnant cow as compared with the non-pregnant cow and are secreted almost entirely by the placenta as shown by Gorski¹²² et al in 1957 when they demonstrated that only a small amount of esogenous estrogen is necessary to bring the ovariectomized heifers into estrus.  Short¹²³ had shown previously in 1956 that the bovine placenta secretes no progesterone showing that it comes from corpus luteum.  Relatively high quantities of estrogens in the late placenta coupled with rather constant levels of progestins in the ovaries¹²⁶ and blood¹²⁷ of the bovine is in contrast to the increasing levels of both groups of steroids in the human placenta during gestation^{128, 129}. Williams¹²⁴ in 1962 has found progesterone in cow's milk in measurable amounts after a definite amount of radioactive progesterone was given intravenously.

            Pigato and Guzzonato¹²⁵ in 1956 did studies on bovine milk from the third to seventh month of the pregnancies.  They studied the milk of five cows with the following results:

Table No. 2

              17-Ketosteroids        20-Ketosteroids               Folliculin            Estrogen

Animal                       in milk                      in milk                        in milk               in milk

           (androgen structure) (progesterone structure)

   #1     44.7 mg. per liter         4.0 mg. per liter              0.596 mg./liter   1.913 mg./liter

   #2     43.2   "    "     "            5.1   "     "     "                0.610   "      "     2.225   "      "

   #3     41.9   "    "     "            7.3   "     "     "                0.796   "      "     2.770   "      "

   #4     40.4   "    "     "            8.1   "     "     "                0.796   "      "     3.164   "      "

   #5     35.8   "     "    "            9.6   "     "     "                0.906   "      "     3.123   "      "

            Further study of cow's milk shows the comparison with human milk in the following table¹³⁰.

Table No. 3

	Protein	Fat	Lactose	Ash Salt	Water
Human	1.4%	3.7%	7.2%	0.2%	87.5%
Bovine	3.4%	3.9%	4.9%	0.7%	87.1%

  

            It is seen here that the ash content of bovine milk is three and a half times that of human milk which is 7 Gm. per liter; of this 1.37 to 1.94 Gm. is sodium chloride¹³¹.  It is also seen from the above table that a liter of cow's milk contains about 40 Gm. of fat.

            Milk also contains 0.6 gamma of cobalt per liter and 540 gammas of iodine¹³¹.

            Meyrowitz et al¹¹⁹ in 1938 made a study of milk-drinking habits of 5227 boys and girls 11 through 18 years of age.  This was conducted in upper New York City.  Of this number, 46 per cent were boys and 54 percent were girls.  They found that 88 per cent of the boys and 80 per cent of the girls were milk drinkers.  Those findings are shown in the two following tables.

Quantity Taken Daily

                                                                Male               Female

            4 glasses milk daily     24.5 per cent   20.5 per cent

            5      "        "       "        10.0   "     "        4.3   "     "

            6      "        "       "          7.2   "     "        1.1   "     "

Median Number of Glasses Milk consumed Daily

Age                 Glasses Daily              Age Distribution of the 5227 Boys and Girls

13 or less           2.9 glasses                                         7.2 per cent

14                      2.7      "                                             15.6  "     "

15                      2.6      "                                             25.4  "     "

16                      2.3      "                                             29.2  "     "

17                      2.2      "                                             17.0  "     "

18                      1.8      "                                               4.6  "     "

PART II

The Tabulated Observations of the Study of 1088 Cases of Acne Vulgaris

Age of Onset

            As is shown in Table No. 4A, the earliest appearance of acne lesions in the female was 4 years of age while in the male as shown in Table No. 4B it was 9 years of age.  No cases were found in the male after 21 years of age while an occasional female appeared with onset of comedones as late in life as 25 to 41 years.  The male overtook the female at the age of 13 years in the number of onset of acne and continued through the 17^th, when they matched.  After 17 years of age the females had more initial onsets than the males.  Forty-one and a half per cent of the 337 male patients had their onset of acne at 13 and 14 years of age.  In the female the greatest percentage of onsets was in the years 12 and 13; this represented 30 per cent of the 712 female patients.

Table No. 4B

337 Males:  Age of Onset

Years of Age               7      8      9      10      11      12      13      14      15

No. of Cases               0      0      2        5       12      33      70      71      55

Percentage of Cases                  0.6   1.47    3.56   9.8     20.4   21.1   16.3

Years of Age               16      17      18      19      20      21      22

No. of Cases               41      26      12        4        4         2      0

Percentage of Cases    12.2   7.7    3.56    1.17   1.17   0.59

Table No. 4A

712 Females:  Age of Onset

Years of Age               3       4       5       6       7       8       9       10       11       12

No. of Cases               0       1       0       1       1       8      15      32       82       95

Percentage of Cases    0     .14      0     .14   .14    1.12   2.1     4.5     11.5    13.3

Years of Age               13      14      15      16      17      18      19      20      21

No. of Cases               118     84      84      42      50      29      15      15      12

Percentage of Cases    16.6   11.8   11.8    5.9    7.0     4.07    2.1     2.1     1.68

Years of Age               22       23       24       25       26       27       28       29       30       31

No. of Cases                 3         9         0         3         2         2         1         0         0         1

Percentage of Cases    0.42    1.26      0      0.42     .28      .28      .14        0         0      .14

Years of Age               32      33      34      35      36      37      38      39      40      41      42

No. of Cases                 1        1        2        1        0        0        1        0        0        1        0

Percentage of Cases    .14      .14     .28    .14       0        0      .14       0        0      .14       0

Table No. 4

Comparison of 337 Males and 712 Females as to Their Ages at Onset of Acne

Years of Age               3       4       5       6       7        8        9       10      11

Males Percentage                                                               0.6    1.47   3.56

Females Percentage             .14            .14     .14    1.12    2.1     4.5    11.5

Years of Age               12       13       14       15       16       17       18       19

Males Percentage        9.8      20.4    21.1    16.3    12.2    7.7     3.56    1.17

Females Percentage     13.3     16.6    11.8    11.8     5.9     7.0     4.07    2.1

Years of Age               20        21        22       23       24       25       26       27

Males Percentage        1.17    0.59

Females Percentage     2.1      1.68     0.42    1.26     0     0.42     0.28     0.28

Years of Age               28       29       30        31       32       33       34       35

Males Percentage

Females Percentage     0.14       0        0       0.14    0.14    0.14    0.28    0.14

Years of Age               36       37       38       39       40       41       42       43

Males Percentage

Females Percentage       0          0     0.14       0         0      0.14       0         0

The Number of Years Acne Present Before First Medical Visit

            Table No. 5A shows the number of years the male patients had their acne before the first visit.  Over ten percent came in during the first year of the eruption; 29 per cent came in after having the condition a year, so that over one-third of the male patients saw the physician by the end of the first year.  None of the males had acne over sixteen years before seeking treatment.  Ninety per cent sought attention within five years.

Table No. 5A

332 Males:  Years That Acne Was Present Before First Visit

Years Acne Present           Within Year        1        2        3        4        5        6        7

No. of Patients                                        34           97      92      31      25      20      13        5

Percentage of All Patients        10.5        29.2    27.7    9.3    7.5      6.0    3.9      1.5

Years Acne Present                      8           9       10       11       12       13       14       15      16

No. of Patients                                         3           2         7         4         1         0         0         1        1

Percentage of All Patients          0.9       0.6      2.1      1.2       .3         0         0        .3       .3

Table No. 5B shows that 10 percent of the females also sought attention before the end of the first year.  But during the first five years only 75 per cent of the females are accounted for as compared with 90 per cent of the males for this same period.  Also the females continued having their first visits for seven years longer than the males.  The longest time for a female to have her eruption before her initial office visit was 23 years.

Table No 5B

691 Females:  Years That Acne Was Present Before First Visit

Years Acne Present                 Within a year         1         2          3          4          5         6

No. of Patients                                                72            126      116       82       74        48       41

Percentage of All Patients                  10.4       18.25    16.8    11.85   10.7    6.95    5.93

Years Acne Present                     7          8          9         10         11         12         13         14

No. of Patients                                       19        18       11         23         12          9            3           6

Percentage of All Patients      2.75      2.6       1.6       3.33      1.74       1.3       0.39     0.87

Years Acne Present                    15       16       17    18     19       20      21      22      23     24

No. of Patients                                       10        3        6       2       3         4         0        2        1       0

Percentage of All Patients        1.45    0.43    .86    .29    .43     .58        0      .29    .145     0

            Table No. 5 shows the percentage comparison of males and females for the years the acne was present on their first visits.  It will be seen that 18 per cent of the females had their acne for a year before receiving medical care as compared with 29 per cent of the males.

 Table No. 5

Comparison of Initial Visits of Males and Females After Onset of Acne

Years Before First Visit            0         1         2         3         4         5         6

Males Percentage                    10.5    29.2    27.7     9.3      7.5      6.0      3.9

Females Percentage                 10.4   18.25   16.8   11.85   10.7    6.95    5.93

Years Before First Visit             8         9         10         11         12         13         14         15

Males Percentage                    0.9     0.6        2.1       1.20        0.3         0           0         0.3

Females Percentage                 2.6     1.6       3.33      1.74       1.3        0.39      0.87     1.45

Years Before First Visit          16      17      18      19      20      21      22      23      24      25

Males Percentage                    0.3       0        0        0        0        0        0        0        0        0

Females Percentage                 .43      .86     .28     .43     .58       0      .29     .14       0        0

Age of Patient at First Visit

            In addition to the tabulation of the age of onset of the acne and the years the condition was present before the first visit, the patients' ages when they first came to the dermatologist were analyzed.  The mode was determined for both sexes for the age at first visit when the greatest number came to the physician.  The ages 14, 15, 16, 17, and 18 years in the male all had about the same number of first visits.  The number at these ages totaled 67 per cent of all the male patients seen.  The range of ages of first visits extends from 9 to 32 years.  The mode was 15 years, 16.3 per cent of these 362 males were seen at this age.

Table No. 6A

362 Males:  Age at First Visit

Years of Age               6       7       8       9       10       11       12       13       14       15       16

No. of Cases               0      0       0       1         0         1       10       22       43       59       40

Percentage                   0      0       0     .552      0     .276    2.76     6.1    11.86   16.3    11.0

Years of Age               17       18       19       20       21       22       23       24       25       26

No. of Cases               52       48       23       16       11        7         8          1        6         8

Percentage                   14.4   13.2    6.35    4.42     3.4     1.93    2.51     .276   1.66     2.51

Years of Age               27     28     29     30     31     32     33     34     35     36     37      38

No. of Cases                  2       1       1       0       0       1       0       0       0       0       0        0

Percentage                   .55    .276   .276    0       0    .276     0       0       0       0       0        0

            The range for the age at the first visit for the females is from 6 years to 44 years as seen in Table No 6B.  Forty-eight percent of the females were seen from the ages of 14 to 18 years inclusive, while 67 per cent of the males were seen within the same five year period.  Sixteen years of age was the mode for the female?age of greatest number of patients first seen.  It also represents the age of 10.4 percent of the group seen.

Table No. 6B

713 Females:  Age at First Visit

Years of Age               6        7        8        9        10        11        12        13        14        15

No. of Cases               1        0        3        4         8         14        31        48        57        73

Percentage                   .138    0      .42    .56      1.12    1.96      4.35     6.73      8.0      10.2

Years of Age               16       17       18       19       20       21       22       23       24       25

No. of Cases               74       70       53       43       32       29       28       20       21       19

Percentage                   10.4   9.8    7.43     6.0      4.5      4.7      3.94     2.8      2.94    2.66

Years of Age               26       27       28       29       30       31       32       33       34       35

No. of Cases               8        17       11        8        11         4        6        5           6        1

Percentage                   1.12   2.38   1.55    1.12     1.55     .56     .84      .7         .84     .14

Years of Age               36      37      38      39      40      41      42      43      44      45      46

No. of Cases                 2        2        1        0       2        0        1        0        1

Percentage                   .28     .28     .14       0     .28       0      .14       0      .14

            For comparison Table No. 6 shows the percentage of the number of patients of each age group of both sexes which were seen at the first visit.

Table No. 6

Comparison Percentagewise of Age of 362 Males and 713 Females at First Visit

Years of Age                  6         7         8         9         10         11         12         13

Male Percentage                                            .552        0       .276       2.76      6.1

Female Percentage      .138       0       .42      .56       1.12     1.96       4.35     6.73

Years of Age                 14         15         16         17         18         19         20

Male Percentage          11.86     16.3     11.0      14.4      13.2      6.35       4.42

Female Percentage        8.0       10.2     10.4       9.8       7.43        6.0        4.5

Years of Age                 21         22         23         24         25         26         27

Male Percentage          3.4        1.93      2.51      .276     1.66      2.51       .55

Female Percentage      4.7        3.94       2.8       2.94     2.66      1.12      2.38

Years of Age                 28         29         30         31         32         33         34         35

Male Percentage          .276      .276          0          0        .276         0           0           0

Female Percentage      1.55      1.12       1.55      0.56      .84        .70        .84        .14     

Years of Age                 36       37       38       39       40       41       42       43       44       45

Male Percentage

Female Percentage      .28       .28      .14        0      .28         0       .14         0      .14         0

Menarche in Relation to Onset of Acne

            Of the 328 young women with acne whose history of onset of menarche could be obtained, 24 or 7.3 per cent had not yet shown signs of menstruating by the time of the onset of acne.  Of the whole group all had had menarche by the age of 17 years.  As shown by Table 7, the youngest to menstruate was nine years.  The greatest number had onset of their menses at twelve and thirteen years of age.  Table 7 also shows the number of patients of various ages in this group whose onset of acne was at the different age levels.

Table No. 7

328 Females:  Age at Menarche in Relation to Onset of Acne

Age at Menarche                        0        8        9        10        11        12        13        14       15

Number of Acne Patients

    with Menarche                    24        0        3        12        71        95        94        19         7

Number with Onset of Acne

   in Above Age Group                       3       10        18        53        60        63        39    &nb