4 Amenorrhoea and dysfunctional uterine bleeding in puberty

4

Amenorrhoea and Dysfunctional Uterine Bleeding in Puberty G. BETTENDORF F. LEIDENBERGER

Regular uterine bleeding occurring at four-week intervals is the key symptom for normal ovarian function. It is one of the symptoms of the functional integrity of the hypothalamic-pituitary-ovarian axis. In the hypothalamus, gonadotropin releasing hormone (Gn-RH) is synthesised and released into the pituitary gland via the portal vessels. The pituitary, in turn, produces and releases follicle stimulating (FSH) and luteinising hormone (LH) in a characteristic cyclic pattern, if functionally intact and properly stimulated. FSH and LH exert their effect in the ovaries, reaching their target organ via the general circulation. Three synchronised, yet distinguishable effects can be observed: cell growth, tissue differentiation and steroidogenesis. In the functional compartments of the ovaries oestrogens and progesterone are synthesised and secreted as the main steroids in proper amounts and at appropriate times. These sex steroids are known to have specific effects on the genital tractfallopian tubes, uterus and vagina, preparing this organ system for egg transport, sperm migration and implantation of the fertilised egg. Oestrogens cause proliferation of the endometrium and progesterone induces secretory transformation of the proliferated endometrium. If no conception and nidation occurs, regression of the corpus luteum takes place accompanied by a fall in oestrogen and progesterone secretion. This event leads to endometrial breakdown and to menstrual blood flow. Apart from this and other effects the ovarian steroids act as a messenger system in the positive and negative feedback mechanisms of the hypothalamic-pituitary-ovarian axis, modifying its functional state. Any disruption of this circuit will lead to anovulation with consequent dysfunctional uterine bleeding or with amenorrhoea. Mechanical causes of malformations of the genital tract have to be excluded if amenorrhoea is taken as a symptom of dysfunction of the hypothalamicpituitary-ovarian axis. Amenorrhoea is defined if no menses at all have been observed by the age of 18 (primary amenorrhoea), or if no bleeding has occurred for at least three cycle lengths in an individual who has been menstruating before (secondary C!illics in Endocrinologv and Metabolism

Vol 4, No. I. March 1975.

89

90

G. BETTENDORF AND F. LEIDENBERGER

amenorrhoea). On the other hand, dysfunctional bleedings are defined as uterine bleedings in anovulatory conditions, which are usually irregular in time, length and intensity 8,29.

AMENORRHOEA Abnormal Differentiation of the Genital Tract During embryonic and fetal life the genital tract (tubes, uterus and upper part of the vagina) is developed through union of the miillerian duct system. Non-union or more or less complete inhibition of mullerian duct formation results in a variety of malformations. Among these the Rokitansky-Kusiner syndrome is characterised by complete absence of the vagina and a rudimentary bipartite uterus with normal fallopian tubes and normal ovaries. These patients have a normal onset of puberty with primary amenorrhoea being the only symptom. Normal sexual performance can be achieved in these patients by surgical construction of an artificial vagina. Obviously, sterility and amenorrhoea are permanent. Other patients exhibit partial obliteration at different segments of the MUllerian duct system with an imperforate hymen, obliterated vagina or cervix as a result. In most cases, uterus and ovaries are normal and the endometrium reacts to the ovarian stimulus by cyclic proliferation and shedding. The obstruction of the menstrual flow results in increasingly painful distention of the organs proximal to the obstruction (haematokolpos, haematometra, haematosalpinx or even haematoperitoneum). Patients with such obstructions of the lower part of the miillerian duct system experience painful attacks at monthly intervals (molimina menstrualis). As early as possible they should be treated by surgical incision or other appropriate surgery to ensure normal menstrual outflow 4,9, 13,20,41.

Endometrial Failure Asherman's syndrome This syndrome is usually seen in adults following' an overzealous curettage resulting in destruction of the endometrium. A similar impairment of the endometrium can be produced by some rare infectious diseases, such as tuberculosis and schistosomiasis. Occasionally, endometrial restitution can be achieved by systemic or local application of high doses of oestrogens, if intact endometrial residues are leftt.

Occult regression of the endometrium (silent menstruation) In very rare cases normal endometrial proliferation can be observed; however, despite normal corpus luteum function, no endometrial shedding occurs at the expected time of menstruation. The cause of this abnormality is unknown. The fertility of patients with this peculiarity is reported to be unimpaired.

AMENORRHOEA AND DYSFUNCTIONAL UTERINE BLEEDING IN PUBERTY

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Genetic Defects and Abnormal Sex Differentiation Associated with Amenorrhoea Testicular feminisation syndrome (hairless women syndrome)

This clinical picture of a male pseudohermaphroditism is characterised by female external genitalia and normal secondary sex development without pubic and axillary hair growth. A nornial or short vagina is present, or-in exceptional cases-absent. There is no miillerian duct development. Testes are found either in inguinal hernias or, less frequently, intra-abdominally. This clinical entity is found in one in every 2000 to 20000 newborns. There is an increased familiar incidence of testicular feminisation, especially in phenotypically female sisters (incidence of I :3) and in the offspring of a normal sister of such patients (I :6). The nuclear sex is always chromatinnegative, and the chromosomal sex found to be XY. Mosaicism has not been observed in this syndrome. CLINICAL ASPECTS. Frequently diagnosis is made before puberty, when the patient is operated for inguinal hernias, or after puberty, when she is admitted for primary sterility and amenorrhoea. Characteristic clinical features are well developed female secondary sex characteristics with normal female body proportions and fat distribution pattern, as well as normal breast development. Axillary and pubic hair is absent, or scant (hence 'hairless women'). The external genitalia are female, the vagina ends blind as a cuff and frequently is shorter than average. There is no uterus nor tubes. Gonads are found mostly in inguinal hernias, or less frequently intra-abdominally and on histological examination are found to be testes. Their histological appearance is variable, with tubules of varying diameter and Sertoli cells. A consistent finding is the absence of mature germ cells. Leydig cells are more abundant than in normal testes. Suggestive of testicular ferninisation, but offering no proof of it, is the histological finding of Pick's adenomas. Because of the propensity of these testes to develop malignancy (10 to 20 per cent), surgical removal and hormone replacement therapy is recommended after puberty. On both clinical and laboratory grounds, there is no doubt that these testes have endocrine function, since a eunuchoid appearance develops if the testes are removed before puberty. Also, climacteric symptoms develop after removal of these testes in adults, if no replacement therapy is initiated; in addition, atrophy of external genitalia and of breasts and general involution occur. The hormonal pattern observed is rather uncharacteristic, with oestrogen levels higher than in normal males, and 17-ketosteroids higher than in normal females. Gonadotropin concentrations are in the normal range or slightly elevated. The plasma levels of testosterone are in the normal male range while dehydroepiandrosterone levels are reported to be high. Plasma clearance and metabolism of plasma testosterone are normal. This clearly shows that these genetically and hormonally normal males do not react to normal levels of androgens. Because of their complete refractoriness to androgens in the critical stages of sex differentiation (7th to 8th week of pregnancy), development is female. The exact mechanism of androgen refractoriness. however, is not yet known. There are, for example, conflicting

\0

IV

Table 1. Synopsis of various forms oj intersexuality associated with amenorrhoea

Syndrome

Pathogenesis! aetiology

Genetics

GonadsP

Mullerian duct inhibitory factor

Genitalia External

For comparison: normal male normal female

XY XX

T 0

-+e

Mb F

Penis Clitoris

Male pseuOOhermaphrodiles Complete form Complete of testicular refractariness feminisation to androgens

XY

T

-+

F

Clitoris

Incomplete form of testicular feminisation (Reifenstein's Partial responsiveness syndrome) to androgens

XY

T

-1

spadia

Pseudovaginal perineoscrotal hypospadia Swyer's syndrome

Temporary loss of androgen stimulation to external genitalia Early testicular degeneration with toss of Mullerian inhibition

M hypo-

Small penis

+ Tubes

Sex

-+

-+

e

M

(oj

"

Fertility Therapy

-+

'e"

F

+

e

F

0

oestrogen replacement

a

M

e

Removal of testes after puberty, androgen replacement

M/F

(+) e

Removal of testes after puberty,

Small

XY

XY

T

sa

-+ e

Ambiguous hypo-

spa dia

enlarged clitoris

0 til

penis,

e

a

tTl

Surgery

-l -l

tTl

Z 0

F

Clitoris

(vanishing testis syndrome)

Degeneration/absorption of testes after early function

XY

e

-'-

M

Small penis

CUterine hernia syndrome

Isolation and failure of Mullerian inhibitory factor

XY

T

e

M

Penis

<:Anorchia

Uterus

Vagina

+

+

F

"

"

M

"

-+

+

M

+

e

Gonadectomy. oestrogen replacement

Androgen replacement

0

:::c

'Tl

> Z

0 :"1

r-

tTl

Surgery

S tTl

Z

til

tTl

:::c 0

tTl

:::c

:>

Table 1:- Continued. Synopsis 01 various lorrns oj interscxaaiitv associated with amenorrhoea

Syndrome

Pathogenesis,' aetiology

Genetics

Gonads lJ

Mullerian duct inhibitory factor

~

rn

Genitalia

Z

o

Uterus External

Vagina

-i- Tubes

Sex

Fertility Therapy

:>= :>=

::t:

o

Female pseudaherrnaphrodites Congenital adrenogenita l syndrome in females Enzyme defects. Pseudohermaphroditism induced bv maternal or exogenous androgens Tru(~

xx

Materna! or exogenous excess of androgens

xx

( .~" I

Replacement with cortisol. surgery

( ,)

Surgery. rreatrnenr of hirsutism with antiandrogens

Enlarged :~

()

o

rnbiguous

clitoris

A.rnhiguous

Enlarged clitoris

Ambiguous F or M

Pe rns 01 clitoris

F

CliLlHI';'

F(MI

+

+

FfMI

phroditism Gonadal dvsgoncsis Turner s syndrome

Genetic

Mixed gonadal dysgenesis

XX.XYor 0'1' or mosaics 0 and T

xo

~(j

Mosaics

Streak

(loss of

ovary no primordial cells

long a rrr»,

Genetic

of X)

Genetic

XX in gonads XO in other body cells

Turner phenotype

with reproductive capability

z

o c

-< Vl

""c: (j

Heterogenous aetiology

Other forms of gonadal dysgenesis (rnosaicisms t

:> :>

z

hrr maphrodirvs

True herma-

-+-.:(l

Genetic Genetic

( Trrojo-x-females

Genetic

Mosaics

r

xv

'0

M+ F

Rept uceme n t

5z

:> r-

...,c: tTl

o

F

t-

Clitoris

replacement

F

c:Z

m

tll tTl tTl

o tissue in SG

T

(females)

o

XXX

o

L

-.j..

-'

r-

(males)

XX

t-- .'H

Her-none replacement

Oestrogen

"

F

Tt-O

Noonan's syndrome (Turner's appearance)

+-

m

+

Clitoris

+

T

Clitoris

"

Removal of streak gonads, hormone replacement

(penis)

+10

4- / n

F'M

o

M

Penis

e

e

M

+

"

F

Clitoris

+

1-

"

Clitoris

+

+ +

F

F

F

(+1

"

+10

Ambiguous

+ "

"

= present: {'l = absent. v T = testes ; 0 _-:.- o varies ; OT ----:-- ovotestes; S = streak : SG·-=-: streak gonad. bM = male: F ~c female. "These syndromes are included for the sake of completeness (normally they are not associated with amenorrhoeal.

o Z o Z "CI c: tll

...,~ -<

\0

W

94

G. BETTENDORF AND F. LEIDENBERGER

results in the literature as to the role of an enzyme defect (5a-reductase deficiency) inhibiting conversion of testosterone to dihydrotestosterone. As documented by the absence of uterus and tubes, the other factor necessary for normal male development, the so-called miillerian inhibiting factor, is active during early sex differentiation. With complete refractariness to androgen, sex assignment at birth presents no problem. However, in cases of partial response to androgens, external genitalia may be ambiguous or such as to allow male sex assignment. In these cases hypogonadism will then be more evident at puberty, when feminisation and gynaecomastia develop. This syndrome of partial testicular feminisation (Reifenstein's syndrome) is transmitted in the same way as the complete form of testicular feminisation. If, in these cases, sex assignment has been male, androgen replacement therapy is indicated after puberty to correct the relative androgen deficiency. Both the complete as well as the incomplete form of testicular feminisation can easily be differentiated from other forms of intersexualism on both clinical and chromosomal grounds (Table 1)5,7,9,20,21,23,33,36,38.

Gonadal dysgenesis The heterogeneous group of phenotypically female patients with the symptoms of gonadal dysgenesis has in common absence of primordial germ cells in gonads which usually have streak appearance to a varying degree. Patients with gonadal dysgenesis can be classified according to their clinical symptomatology into a group with extragonadal malformations of varying number and localisation (Table 2) (Turner's syndrome) and a group without extragonadal malformations. This clinical classification can, to some extent, be correlated with the chromosomal pattern, and it is foreseeable that further refinement of genetic methods will result in more detailed clinical classification. Gonadal dysgenesis is found in 10 to 25 per cent of all patients with primary amenorrhoea. The estimated rate of occurrence in a normal population is one in 2000 to 10 000. It is likely that in the groups of gonadal dysgenesis studied, patients with extragonadal malformations are overrepresented, because they are more readily recognised. Patients with gonadal dysgenesis without extragonadal malformations are approximately 50 per cent chromatin positive, the other 50 per cent, chromatin negative. If positive, they exhibit an XX chromosomal pattern with one X chromosome possibly being inert or with some other functional damage not recognisable by morphological means. The chromatin negative forms show an XY constellation with the Y chromosome being inert. Gonadal dysgenesis patients with extragonadal malformations are more frequently chromatin negative than positive (3:1). The chromatin negative patients constitute the largest group with the chromosomal constellation 45X clinically characterised by the classical signs of Turner's syndrome (Table 2). The chromatin positive cases show various forms of mosaicism (XX, X; XXX,X; XXXX,X; XXX,XX,X etc.) and/or structural peculiarities of the X chromosome. Finally, there are patients reported with an XX constellation

AMENORRH OEA AND DYSFUNCTIONAL UTERINE BLEEDING IN PUBERTY

95

Table 2. Clinical symptomatology in gonadal dysgenesis' Occurrence rate Clin ical symptom

XO

Mosaicism

Short sta ture Prim ar y amenorrhoea Inverted hair growth Low implantation of hair Genital hypoplasia Abnormal nails Short neck Breast hypoplasia Shield chest Scarce pubic ha ir Pigmented nae vi Malformation of ea r lobe s Lymphoedema at birth Auditive problems Short fingers Renal problems (malfo rmatio ns) Webbed neck Abnormal facies Arched palate Epicanthic folds Micrognathia Laterally positioned nipples Low implantat ion of ear lobes H ypertension Oblique eye lids Cubitus va lgus Overweight Ptosis Abnormal vision Mental retardatio n

97

93

95

87 79 83 79 67 52 78 64

93 91

118

87 86 84 83 81

69 65 57 50 48 48 47 47 44 37 36 31

29 26 26 25 21 21 14 12

68 57 50

29 43 37 31 21

38 29 38 7 7

29 10

25 21 20 21

o

II

"Th is table is based o n data from : Matt evi et a l (1971) a nd Maje wski et al (1974).

in blood cells (Ieucocytes) and 45X constellation in tissue, or, rarely, with 45X pattern in bod y tissues and clinically Turner's symptoms and an XX pattern in the gonads. The se patients are the excepti onal Turner syndrome patients who can be fertile . By strict definition these latter patients have, of course, no gonadal dysgenesis but are included here because of their clinical appearance. The feature common to all form s of gonadal dysgenesis is the pre sence of gonadal rudiments with ovarian stroma but lack of follicular tissue. Corresponding to the rud imentary development a nd a bsent hormonal funct ion of the streak gonads, the uterus is severely hypoplastic and the vagina short and narrow. The external genitalia are hypoplastic with only scant pubic hair. There is primary amenorrhoea. In contrast to th ese findin gs found in practically all form s of gonadal dysgenesis, patients of the two groups with and witho ut extragonadal malformati on ca n well be differentiated on clinical grounds. Patients witho ut

CLINICAL ASPECTS.

96

G. BETTENDORF AND F. LEIDENBERGER

extragenital malformations are of or above average height. Secondary sex characteristics are moderately developed. Patients with the classical Turner's syndrome (45X constellation), on the other hand, show a broad spectrum of facultative malformations, symptoms and peculiarities. These are summarised in Table 2. Other facultative clinical signs are malformation or low position of the ear lobe, red-green blindness, stenosis of the big arterial vessels and others. A frequent finding in atypical forms of Turner's syndrome with signs of virilism (hypertrophic clitoris, hirsutism, low or hoarse voice) is, on histological examination of the gonads, accumulation of hilus cells which are probably the source of androgen production and of the clinical symptomatology. The hormonal pattern of gonadal dysgenesis is usually characterised by high gonadotropin secretion with predominance of FSH (as in postmenopausal women), and low oestrogen as well as J 7-ketosteroid secretion. There is no causal therapy available for the primary amenorrhoea and the sterility; all therapeutic measures are aimed at development of secondary sex characteristics d uri ng or after puberty and maintenance of protein anabolism. This can be achieved by systematic application of either oestrogens or oestrogen-gestagen combinations. Hormonal therapy should be started only when no significant further growth can be expected, according to the bone age and present height (Bayley-Pinneau tables). It is also of c1i nical significance that an increased risk of malignant degeneration of gonadal tissue is known among patients with gonadal dysgenesis, especially those with 'pure' gonadal dysgenesis (chromosomal XY constellation) and with mosaic patterns containing Y chromosomes. The same holds for cases of mixed gonadal dysgenesis with testicular type tissue present 9 , 11,

THERAPEUTIC ASPECTS.

13,20,26,30,37.

Adrenogenital Syndrome Congenital adrenogenital syndrome (CAGS) This disease belongs to the group of enzymopathies which are caused by genetic defects. According to genetic studies the CAGS is transmitted by a recessive autosomal trait. Its rate of occurrence is estimated to be between 1:5000 and 1:70000. Although it is a rare disease, it accounts for approximately half of all infants born with ambiguous genitalia and for about five to 10 per cent of all patients with primary amenorrhoea. PATHOGENESIS. According to the type of enzyme defect various clinical forms of CAGS can be differentiated: I. The 'simple' form of CAGS is enzymatically characterised by a partial C-21.hydroxylase defect, leading to decreased cortisol synthesis and release from adrenals, and to a lesser degree to decreased formation of mineralocorticoids. This latter, however, is at least in the 'simple' form of no clinical consequence. The low plasma cortisol concentration triggers ACTH release from the pituitary which in turn causes adrenal hyperplasia and accumulation of adrenal androgens. If this metabolic block is complete, a severe disturbance of electrolyte metabolism occurs in addition to the virilising effect of the accumulated adrenal androgenic steroids (salt-loosing form of CAGS).

AMENORRHOEA ANI) DYSFUNCTIONAL UTERINE BLEEDING IN PUBERTY

97

2. Other enzyme defects associated with CAGS are a deficiency of a resulting in inability of the adrenal to form mineralo- and glucocorticoids. Instead, weak androgens are formed and found in urine. The clinical picture is characterised by moderate virilisation of females and, with complete block of the 3~-dehydrogenase, by severe electrolyte imbalance. 3. A third enzyme defect is deficiency of an l l-hydroxylase. The metabolic consequence of this block is inability of the adrenals to form Csl l-hydroxylated compounds, i.e., mainly corticosterone, aldosterone and cortisol. Instead, androgens and II-deoxycorticosterone are accumulated, the latter having a hypertensive effect (hypertensive form of the CAGS). 3~-dehydrogenase

CLINICAL ASPECTS. The early fetal exposure of a genetically and gonadally female organism to increased androgen concentrations results in virilisation of the genitalia with consequent clitoral hypertrophy and persistence of the urogenital sinus. Depending on the onset and the degree of exposure to androgens various stages of virilisation can be observed. The androgens secreted by the adenals in large amounts have also an anabolic effect on protein synthesis in general and on muscular growth as well as on bone maturation in particular. Consequently, the typical AGS patients have short stature with male type proportions and well developed musculature. In early childhood their longitudinal growth is above average, but they cease to grow at the age of 10 to 12 years instead of 17 to 19 years. Other virilising effects appearing early in childhood are acne and seborrhoea as well as growth of pubic and axillary hair. On the other side, due to hypothalamic and pituitary suppression by androgens, the ovaries are not stimulated by the pituitary gonadotropins and at the time of puberty no clinical signs of oestrogenic activity are seen: there is no mammary growth and no development of the female secondary sex characteristics. The ovaries show no follicular ripening. There are no clinical signs of cyclic function of the ovaries. According to the underlying metabolic error treatment aims at substitution of cortisol and, if necessary, of mineralocorticoids, as early in life as possible. If treated from birth and in proper dosage, such females can develop normally and start to have regular ovarian function at the time of puberty. Fertility is reported. Even if cortisol treatment is delayed until or beyond puberty ovarian function starts spontaneously. Since substitution with cortisol and mineralocorticoids is no cure but rather a symptomatic treatment, CAGS patients have to be under medical control for their lifetime. An ambiguous external genitalia has to be corrected surgically as early as possible 2 , 3,9, I S, 32.

Acquired adrenogenital syndrome As a rule, this syndrome is attributed to women who during or shortly after puberty develop hirsutism of varying degree, acne and occasionally hypertrophy of the clitoris. The syndrome is accompanied by anovulation and secondary amenorrhoea or other bleeding disorders. Apart from the above signs of mild androgen effects these patients have normal female appearance with normal breast development. The 17-ketosteroid excretion in urine is

98

G. BETTENDORF AND F. LEIDENBERGER

elevated. The reaction of l7-ketosteroids to ACTH stimulation is greater than in normal females. Cause and pathogenetic mechanisms involved are usually poorly understood. There is, however, an exceptional patient who after puberty develops signs of AGS and who is found to have the enzymopathies characteristic of CAGS. In practice, it is generally impossible to differentiate between so-called idiopathic forms of hirsutism and acquired adrenogenital syndrome. On the other hand, it is relatively easy to differentiate hirsutism and signs of virilisation due to androgen-secreting tumours of the adrenals from the hirsutism due to acquired adrenogenital syndrome. In the first case usually extremely high l7-ketosteroid excretions are found with signs of virilisation much more prominent. Also these patients do not react to ACTH stimulation or cortisol suppression therapy with significant changes in the l7-ketosteroid excretion. Before initiation of any therapy, androgen-secreting tumours have to be excluded. Therapy is aimed at restoration of ovulatory cycles and fertility as well as at improvement of hirsutism and acne. After mild cortisol suppression therapy ovulatory cycles can be induced in about 30 to 50 per cent of patients and pregnancy rates are similarly high. If anovulatory cycles persist after adequate cortisol suppression therapy, induction of ovulation can be attempted with clomiphene or gonadotropins. Hirsutism, however, usually does not disappear after cortisol therapy alone, but can be ameliorated with antiandrogens (cyproterone-acetate) or oestrogen-antiandrogen combinations, if fertility is no urgent problem 2, 3,9, 15. Hormonally Active Tumours Masculinising tumours of the ovary ARRHENOBLASTOMAS are rare facultatively malignant tumours of the ovary and have been found in all age groups. They are, however, extremely rare in puberty. 20 to 30 per cent of them are malignant at the time of operation and only some of the arrhenoblastomas are hormonally active. The clinical symptoms in patients with arrhenoblastomas or other androgen-secreting tumours depend on the onset of hormonal activity of the tumour and on the amount and biological activity of the androgens secreted. If such tumours appear during puberty the development of secondary female sex characteristics is disturbed and virilisation occurs. The symptoms to occur first are primary or secondary amenorrhoea, followed by enlargement of the clitoris, hirsutism and deepening of the voice as well as breast atrophy. Due to androgenic suppression of pituitary gonadotropin secretion the contralateral ovary atrophies and amenorrhoea occurs in nearly all cases of hormonally active arrhenoblastomas. The characteristic androgens found are testosterone and dehydrotestosterone. HILUS CELL TUMOURS are extremely rare and only occasionally hormonally active. They can secrete androgens as well as oestrogens. At the earliest they appear in the twenties, more often, however, after menopause. They are never malignant.

AMENORRHOEA AND DYSFUNCTIONAL UTERINE BLEEDING IN PUBERTY

99

of the ovary are masculinovoblastomas, gynandroblastomas (so-called mixed tumours) and gonadoblastomas. They are extremely rare; some of them are able to secrete androgens and oestrogens. Since they practically never occur at puberty or in childhood, they are not pertinent to this chapter.

OTHER OCCASIONALLY MASCULINISING TUMOURS

Feminising tumours of the ovary Granulosa cell tumours, theca cell tumours, and luteomas are oestrogenproducing tumours and can initiate isosexual pseudopuberty or secondary amenorrhoea of short duration followed by irregular and/or long-standing bleedings. Other occasionally hormonally active tumours of the ovary Cystadenomas, cystadenofibromas, Brenner tumours, dysgerminomas and ovarian carcinomas apparently can occasionally produce oestrogens and/or androgens, although this is exceptional. Hormonally active tumours of the adrenals Adrenal adenomas and carcinomas are known to be frequently able to produce androgens and/or oestrogens in variable amounts. In cases of virilisation and feminisation the source of steroid production has to be located. In general, androgen-secreting adrenal tumours are associated with strongly elevated or even excessively high concentrations of urinary 17-ketosteroids. This is in contrast to most ovarian virilising tumours with normal or only slightly elevated 17-ketosteroids and high plasma testosterone and dehydrotestosterone concentrations. Adrenal adenomas and carcinomas are usually autonomous, i.e. their steroid hormone synthesis and secretion does not follow the negative ACTH-steroid feedback mechanism. Tumours producing tropic hormones Production of chorionic gonadotropin (HCG), luteinising hormone (LH), follicle stimulating hormone (FSH), adrenocorticotropic hormone (ACTH) and prolactin by tumours of various locations has been reported. In rare cases they may cause precocious pseudopuberty, irregular bleeding or amenorrhoea. In particular, bronchogenic carcinomas or adenomas and hepatomas have been shown to produce tropic hormones. Also, gonadotropin-producing dysgerminomas and choriocarcinomas associated with precocious puberty have been reported 19,20,25,37,40,43. Functional Amenorrhoea When discussing the various types of amenorrhoea one has to keep in mind that this symptom is only the end point in a variety of conditions ranging from normal function to complete absence of ovarian function. Pathological ovarian function may be reflected by different clinical pictures depending on the stage of individual sexual development at the time of onset and the degree of dysfunction. In addition to the symptom 'amenorrhoea' the development of the secondary sex characteristics is of particular

100

G. BETTENDORF AND F. LEIDENBERGER

importance. With severe ovarian dysfunction beginning early in puberty no further development of sex characteristics can occur. On the other hand, the demonstration of a normal female habitus, developed breasts and normal axillary and pubic hair growth is proof enough that the ovaries must have met at least some basic endocrine requirements, despite the presence of the symptom 'amenorrhoea'. Normally menarche occurs between II and 16 years of age. A delay of menarche beyond the age of 16 is called 'delayed menarche' or 'pubertas tarda'. Absence of signs of early puberty, such as mammary development, pubic hair growth after the age of 16,j ustities a tentative diagnosis of primary amenorrhoea. These cases should be investigated without delay in all details possible, in order to clarify the mechanisms underlying the developmental delay. However, if in a girl whose sexual maturation is beginning, delayed menarche is the only complaint, and no other abnormalities are suspected, postponement of detailed investigation until the age of 18 is justified. Secondary amenorrhoea of variable duration is frequently encountered in adolescent girls and is a reflection of incomplete maturation of the cyclicity of the hypothalamic-pituitary-ovarian axis in this period of life. Application of exogenous hormones will interfere with this maturational process. Also it should be kept in mind that oestrogen or oestrogen-progestagen combination therapy will cure only a symptom and induce bleeding, but will not induce regular cyclic function of the hypothalamic-pituitary-ovarian axis. Amenorrhoea is the result of insufficient oestrogen stimulation of the endometrial growth and transformation by progesterone. Any disruption of the functional circle, hypothalamus-pituitary-ovary, will lead to anovulation with or without amenorrhoea. It is a well established fact that this functional circle is liable to disturbance not only from organs directly involved in sexual and reproductive function, but frequently by other organ systems. This is particularly well documented for diseases of the thyroid gland, the adrenals and for the islets of Langerhans. Liver and kidney disease can cause dysfunction of the ovaries by mechanisms only partly understood. As far as therapy is concerned, it is widely accepted that the function of these organ systems should first be re-established before attempting to influence ovarian function. Even more complex in origin are functional amenorrhoeas which are of psychogenic origin or associated with psychogenic disorders and/or stress situations. Extreme examples of this group of amenorrhoeas are the amenorrhoea of anorexia nervosa and the amenorrhoea encountered under Iifethreatening conditions such as those observed in women in prison or concentration camps. Even minor stress situations can disturb ovarian function (e.g. examinations, travelling, social conflicts, etc.). Aetiologically and prognostically different from these types of amenorrhoea is the functional amenorrhoea associated with voluntary food deprivation, as is frequently seen in young adolescents with overemphasised weight-consciousness. Last but not least, intracranial tumours should always be excluded as a cause of amenorrhoea before a functional amenorrhoea is assumed. Although many proposals have been made to classify amenorrhoea, no satisfactory classification based on aetiological principles is available at present. However, the empirical classification described below has success-

AMENORRHOEA AND DYSfUNCTIONAL UTERINE BLEEDING IN PUBERTY

tOl

fully been used for more than one decade. The parameters for this classification are the quantitative determinations of oestrogens and gonadotropins in urine or plasma. According to gonadotropin levels the following groups can be defined: I. Hypogonadotropic ovarian failure with amenorrhoea. 2. Normogonadotropic ovarian failure with amenorrhoea. 3. Hypergonadotropic ovarian failure with amenorrhoea. In the hypo- and hypergonadotropic group no clinical signs of oestrogenic activity can be found, such as ferning or spinnbarkeit or the typical oestrogen effect on the vaginal epithelium. On the other hand, in patients with a normogonadotropic amenorrhoea the clinical oestrogen effects mentioned above can be demonstrated and oestrogen concentrations are in the normal or low-normal range. Differentiation between amenorrhoeas which are associated with oestrogenic activity and those which arc not is easily accomplished by progestagen administration to the patient: if bleeding occurs, sufficient oestrogen stimulation to the endometrium must have been present. Since fertility or sterility does not pose a problem in the adolescent, treatment difficulties and drawbacks will be discussed only shortly. Causal therapy is aimed at induction of ovulatory cycles followed by normal menstrual bleeding. Unfortunately, the rate of spontaneous ovulatory cycles following repeated induction of ovulation is remarkably low (10 to 20 per cent). Therefore, any attempt to initiate spontaneous cyclic ovarian function by exogenous induction of ovulation should be restricted to one or two treatment cycles, at least in this age group. In hypergonadotropic states no aetiological treatment is possible, because hypergonadotropinaemia, or -uria, reflect primary ovarian failure. Clinical and laboratory examination should exclude chromosomal defects with gonadal dysgenesis such as Turner's syndrome or various forms of mosaicism (see Table 1). In cases of gonadal dysgenesis or premature primary ovarian failure therapy is restricted to steroid (oestrogen or oestrogen-progestagen combinations) substitution, in order to induce or to complete development of secondary sex characteristics or to prevent early climacteric involution. In normogonadotropic amenorrhoea ovulation can be induced in more than 70 per cent of patients by administration of clomiphene. However, as mentioned before, the rate of recurrence of spontaneous cycles after cessation of clomiphene administration is low. H MG/hCG administration is the therapy of choice in hypogonadotropic patients or in patients unresponsive to clomiphene. Subsequent spontaneous cycles, however, are even less frequently seen than in the group of normogonadotropic patients after cessation of therapy, and it is this failure and the potential hazards of gonadotropic therapy (overstimulation), which restrict this type of therapy to those patients with sterility problems. The functional state of the pituitary can be tested by the effect of the synthetic gonadotropin releasing hormone (Gn-RH) on plasma FSH and LH concentrations. The type of pituitary reaction allows differentiation between dysfunctions primarily located in the pituitary and those in the hypothalamus. The secretory reaction of the pituitary to Gn-RH stimulation correlates well

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with the plasma FSH and LH concentrations measured before the stimulation test and with the urinary excretion of total gonadotropins. At least for clinical use, the Gn-RH stimulation tests are of only minor significance because no diagnostic or therapeutic conclusion can be drawn from them other than that drawn already from the determination of gonadotropin concentrations. The Gn-RH stimulation test is, however, an additional useful tool in evaluating hypergonadotropic conditions, because truly hypergonadotropic patients show more pronounced response to application of Gn-RH than normogonadotropic patients. This frequently helps the classification of a patient in one group or another, which is sometimes difficult solely on the basis of gonadotropin concentrations. The reactivity of the hypothalamus and pituitary as a functional unit can be examined by clomiphene administration. However, the result of this stimulation test does not give information over and above what we already know from gonadotropin determinations. Stimulation tests are also in use for testing ovarian incretory activity. With the clinical experience gained over the last decade or two, however, we can safely predict that patients belonging to the hypo- or normogonadotropic group will react either to clomiphene or HMG/hCG treatment. Therefore, the ovarian stimulation tests mentioned give no additional clinical information. Since prognosis of these patients as to their fertility is quite predictable, one is well advised to give no therapy in adolescent girls with norrno- or hypogonadotropic conditions. Instead, it is recommended to wait for self-regulation and to induce ovulation later, whenever pregnancy is desired. The so-called Stein-Leventhal syndrome or polycystic ovarian disease is not included in our classification scheme of amenorrhoea and dysfunctional bleeding disorders. There seems general agreement that this syndrome is no aetiological entity. In addition, the clinical appearance (grey-white enlarged ovaries with smooth surface) and the histology of the ovaries (thickened tunica albuginea) from patients classified as cases of the Stein-Leventhal syndrome have no consequence as far as diagnosis and therapy are concerned. Therefore this syndrome should be eliminated as an entity from our clinical repertoire, despite the fact that polycystic ovaries are frequently found around puberty. It is to be remembered, however, that patients with clinical and laboratory evidence of increased androgenic activity, such as is found also in the Stein-Leventhal patients, are predisposed to overstimulation, when clomiphene or HMG/hCG therapy is attempted. Because of the favourable response of polycystic ovaries to clomiphene and/or HMG/heG there is no justification any more for the tissue wasting ovarian wedge resectione.s- 12,14, 17,20,22,24,29,31,35,39,42,44.

Iatrogenic Amenorrhoea and Other Forms of Induced Amenorrhoea With the widespread use of steroids in various clinical conditions pharmacologically induced amenorrhoeas deserve some attention. Most common among steroid-induced amenorrhoea is the so-called 'post-pill' amenorrhoea encountered in a minority of women after cessation of oral contraception. This type of amenorrhoea is even more frequently observed in adolescent girls suffering from labile ovarian function. Oral contraception with combina-

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tion or sequential preparations should therefore be postponed until regular menstrual bleeding and a biphasic basal body temperature chart indicate stabile ovarian function. Androgenic steroids and progestagens, such as used in the treatment of precocious puberty, can also result in secondary amenorrhoea. Amenorrhoeas have also been seen after use of tranquillisers. A recent observation is secondary amenorrhoea in heroine and morphine addicts 28,34. Physiological Amenorrhoea

While discussing dysfunctional uterine bleeding and amenorrhoea in adolescents one should not forget pregnancy as a rare, albeit possible cause of secondary or, in very rare cases, of primary amenorrhoea in adolescents 10 , 37

DYSFUNCTIONAL UTERINE BLEEDING (JUVENILE BLEEDING) In the broad spectrum of ovarian dysfunctions ranging from normal ovulatory cvcles to amenorrhoea, anovulation takes an intermediate place. Milder forms l;r ovarian dysfunction manifest themselves as a variety of anovulatory uterine bleeding disorders frequently encountered in the adolescent girl, as well as in the climacteric woman. The anovulatory cycle is clinically diagnosed by a monophasic basal body temperature chart (BBT). The corresponding and underlying process of the ovary is follicular maturation with increasing oestrogen production but without ovulatory rupture of the mature follicle. When, later in the process, oestrogenic activity of the follicle decreases, withdrawal bleeding occurs. The bleeding intervals arc usually irregular. In most cases this withdrawal bleeding preceded by an anovulatory cycle is of no further consequence to the young individual and can be considered an intermediate step in the maturation process towards regular cyclic function of the ovaries (Table 3). Table 3. Rate of ovulatory cvcles in different age groups'

Age 12-15 16-18 19-21 22-25 2630

Total 240 (100:>0) 331 (IOO
Anovulatory cycle"

Short luteal phase'

135 (56.2 "0) 131096";,) 93 (37.0 ''0)

82 04.2 °i~) 143 (43.2 "0) 75 (29.9 °i~) 76 (31.5 \,) 55 (13.2 j~)

17 (70 0 ,,)

21 (50",,)

Ovulatory cycle' 23 (9.6 ~:,)

57 (17.2 ~'~) 83 03.1 /~) 148 (61.4 0/0) 342 (81.8,%)

"Data from Doring (1963). "Determined by basal body temperature measurement.

Persistence of an incompletely stimulated follicle for a longer period of time results in production of large amounts of oestrogens. However, after six to eight weeks oestrogen production usually becomes insufficient to keep up with the big demand of the highly proliferated endometrium, or alternatively, follicular regression occurs without preceding ovulation. The clinical

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equivalent is either an oestrogen breakthrough bleeding or a withdrawal bleeding characterised by its intensity and long duration. This type of dysfunctional bleeding which is caused by persistence of an unruptured follicle has high recurrency. For correct diagnosis of this bleeding disorder the patient's history is of importance. These patients are usually seen with intensive bleeding after a bleed-free interval of six to eight weeks. Despite heavy bleeding high oestrogenic activity can be demonstrated in these patients (spinnbarkeit and ferning of cervical mucus, karyopyknotic index of vaginal epithelium). Clinically this bleeding condition has to be differentiated from disturbed uterine or ectopic pregnancy, or rarely from bleeding observed with persistence of a corpus luteum. Bleeding can easily be stopped by administration of oestrogen-progestagen combination therapy. Withdrawal bleeding will occur after cessation of therapy. The following cycle has then to be controlled by measuring BBT and possibly by application of oestrogen-progestagen combinations, if after approximately three weeks, the BBT chart does not indicate ovulation (temperature rise). Alternatively, clomiphene can be given to induce rupture of the mature follicle. One should, however, avoid indiscriminate prescription of commercial oestrogen-progestagen combination pills to a girl who has bleeding disorders of this type. Such treatment would only further block her already labile feedback mechanisms 16,18,28,44. BLEEDING ANOMALIES IN OVULATORY CYCLES

After menarche bleeding intervals are variable. Oligomenorrhoea results if the follicular phase of the ovulatory cycle is prolonged. On the other hand, an unusually short follicular phase will lead to short bleeding intervals (polymenorrhoea). frregularities of the corpus luteum phase are also encountered in this age group. Insufficiency of the corpus luteum is a frequent finding in adolescence. This is characterised by hyperthermia shorter than 10 days, a gradual rise of the BBT over several days (staircase phenomenon) and low plasma progesterone levels. On histological examination an incomplete secretory transformation is revealed; a long-lasting menstrual flow can be the clinical consequence. While corpus luteum insufficiency is a well known cause of sterility, it has no importance in puberty and adolescence. Slight or moderate bleeding occurring rhythmically around the expected time of ovulation is interpreted as 'ovulation bleeding'. Diagnosis can be made by correlating the bleeding to the BBT pattern. This abnormality is thought to be due to low oestrogen secretion in the follicular phase and a fall in oestrogen levels preceding ovulation. A low dose oestrogen supplementation for three to four days around the expected time of 'ovulatory bleeding' will prevent this breakthrough bleeding. Last but not least, all bleeding from the genital tract can be classified as functional after organic causes such as malignancies, polyps, injuries, infectious diseases, etc. have been excluded. This is true regardless of age. Inspection and palpation of the genital organs are mandatory. Under certain rare circumstances even a curettage is necessary16,18,24,44.

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