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

91

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



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

...,~ -

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...
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