This condition is presented as a delay in appearance or nonappearance of menses. It is generally described as nonachievement of puberty during the premenarchal year.
The development of the neuroendocrine controlling mechanism which is responsible for initiating the hypothalamo-pituitary-ovarian axis begins around the 9th to 10th week of gestation.1 The presence of Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) have been identified in the fetal brain tissue.2 The FSH levels rise during the subsequent weeks to a maximum level by 20 weeks gestation. In parallel, the development of the ovary with transition of oogonia to mature graafian follicles occurs and the granulosa cells start developing by 20 weeks of gestation. As gonadotropin receptors have also developed on these granulosa cells, the fetus is now capable of producing endogenous estradiol.3 Estriol and other estrogens are also increasingly produced by the maternal placenta and crossover to fetal circulation. After the 20th week of pregnancy, the serum FSH levels of the fetus start falling in response to increasing estrogen levels circulating in the fetus. The drop in FSH level shows that the feedback mechanism for the Gonadotropins (GTH) is already intact and functional during fetal life thus proving the presence of gonado hypothalamo-hypophyseal (HT-HP) axis. At birth, the major source of estrogen (i.e. the placenta) is removed, and the only source is that from the fetal ovary which produces relatively small amounts of estrogen. However, just as estrogen withdrawal leads to elevated levels of FSH in the adult, the FSH rises in the neonate also and remains elevated at castrate levels until the child is 6–9 months of age. At birth the fetus also shows competence of the endometrium to respond to increasing levels of estradiol brought into the fetus by the mother; withdrawal of estrogen from maternal circulation into the fetus results in fall in the estrogen level, and endometrial shedding of the newborn occurs. Quite frequently from the time the child is 9-month-old until the age of 2 years, the FSH level gradually declines and becomes almost undetectable.4
The plasma levels of FSH and LH hormones remain low until the end of the prepubertal stage. As puberty changes become evident, the FSH levels rise and appear to reach a peak stage about the time of menarche. During the early onset of pubertal changes, FSH and LH are usually released mainly at night.
Fig. 1.1: Serial serum concentration of FSH and LH in perimenarchal girls(Adapted from Faiman and Winter (1974) and simplified for the purpose of understanding)
To start with, the level of FSH is always higher than that of LH but with advancing puberty, the LH production starts increasing and the level of the two pituitary gonadotropic hormones become almost equal. The values of serum FSH and LH from preadolescence through the menarche and postmenarchal periods is illustrated in Figure 1.1.5
There has been much speculation upon reasons for delay in the effective hypothalamo-hypophyseal function when both these structures are clearly capable of working at an earlier age. It seems likely that the most significant fact here is the low setting of the hypothalamic gonadostat. Suppression of the hypothalamus is possible with relatively small amounts of estrogen which the child's ovaries produce. Gradually as puberty approaches, the degree of sensitivity seems to lessen. This results in release of hypothalamic GnRH which stimulates the release of GTH of the pituitary leading ultimately to stimulation of sufficient ovarian activity to bring about the physical changes of puberty. It has also been seen that in children born with no gonads, e.g. in cases of pure Turner's syndrome, where there is literally no estrogen at all, there is much greater production of FSH and LH than in normal children suggesting that the lack of even a small amount of estrogen which a normal child produces is sufficient to release the hypothalamus from inhibition.4 Grumbach et al have shown that giving small amounts of estrogen like 2 micrograms of ethinylestradiol for 5 days in these children has produced significant reduction in FSH and LH. It has also been shown that as puberty approaches, larger doses of ethinylestradiol (around 10 micrograms) are necessary to bring about inhibition of FSH and LH and by the time puberty is reached even these are inadequate. It has been suggested that one reason for diminution in the sensitivity of the hypothalamus to small doses of estrogen may be the rising levels of adrenal androgens from age of 7 or 8 onwards. It is possible that the higher centers may modify the activity of hypothalamus from early years of childhood, e.g. pineal body and limbic system have all been shown to have some involvement in the sensitivity of HT to estrogen. However, one has to admit that the real importance of these higher centers in the physiology of normal puberty is not completely understood.
Factors Predicting Onset of Menarche
Since puberty involves the psychosomatoskeletal changes that appear just a few years before the actual onset of menses, the calendar of events has been noted to be as follows. The table below shows physiological changes during puberty. The physical features are the breast growth, pubic hair growth, axillary hair growth, growth spurt and menstruation itself.
Breast growth - Thelarche
Pubic and axillary hair growth – Adrenarche
Menses and growth spurt
This is true in case of 50% of children. The chronological order may not always be as given above. These are subject to changes depending upon each individual, e.g. a child may have axillary hair growth before breast growth starts and sometimes growth spurt occurs even before breast growth starts. However, menstruation usually comes before the age of 16 and Secondary Sexual Characteristics (SSC) should appear before the age of 15. Any delay beyond these years should be treated with suspicion.
The child has the highest velocity of growth between the age of 0 to 2 years and this may be anywhere between 7 to 13 cm per year. See growth rate as given in the graph below (Fig. 1.2).
From the second year onwards it slowly reduces so that by the 5th year of life the velocity of growth may be between 5 to 9 cm per year and then as the puberty changes start appearing from the age of 11 to 13; a sudden spurt in the velocity of growth is seen again ranging anywhere between 6 to 10 cm per year. From 13th to 14th year onwards, the spurt goes down to about 2 to 4 cm per year and eventually stops.
Premature thelarche or breast development without any other sign of puberty is very rare. Growth of pubic and axillary hair, however, may be initiated as the first change of puberty. This change is caused by the increased production of adrenal androgen and this could occur even before the gonad matures. The increase in adrenal cortical function is seen by a rise in the levels of dihydroepiandrosterone (DHEA), dihydroepiandrosterone sulfate (DHEASO4) and androstenedione.
Thus, the beginning of adrenarche precedes the linear growth spurt by 2 years. The rise in estrogen and GTH levels in early puberty, and appearance of menarche at mid-puberty run parallel to the growth spurt. Dissociation of the sequence of events can occur in certain pathological states. These must be identified. Premature adrenarche might appear as precocious appearance of pubic and axillary hair which arouses suspicion of late onset or Congenital Adrenal Hyperplasia (CAH).
In hypergonadotropic hypogonadism, as seen in gonadal dysgenesis or Turner's syndrome and hypogonadotropic hypogonadal state such as Kallmann's syndrome, adrenarche might appear despite the absence of gonadarche. Children with Addison's disease treated with cortisol may show gonadarche in the absence of adrenarche. The hormone replacement with cortisone can take care of the general metabolic requirements of the patient. However, since the hormones required for initiating adrenarche like DHEA and DHEASO4 are missing, they may not develop adrenarche at all.
Study of ovaries in the prepubertal age becomes a very interesting matter. There is a gradual increase in size and number of ovarian follicles with age so that after 8 to 8.5 years before any signs of puberty appear, a multicystic ovarian pattern may be seen on ultrasound examination. One may see more than 6 follicles in each ovary spread uniformly all over the ovary and each cyst may be about 4 mm in diameter. The follicular development of the ovary is controlled by the hypothalamic pituitary gonadal axis.6 Multicystic morphology in a girl with delayed puberty denotes that puberty is likely to occur soon. If this pattern is absent, it means that either the gonad is not responsive to pituitary stimulation (hypergona-dotropic hypogonadal state) or that the gonad is not being stimulated by the pituitary gland denoting a hypogonadotropic hypogonadal state. The former is a more serious condition than the latter as will be explained in due course in this chapter.
Of all the factors that determine the timing of puberty, the genetic factor is the most important. Other factors that are likely to have an influence are the geographic location, exposure to light, general health and nutrition and psychological factors. Children with a family history of early puberty start early.7 Children closer to the equator or those at low or high altitudes, those in urban areas and mildly obese children attain puberty earlier than children with opposite factors. There is a fairly good correlation between timing of menarche of mothers and daughters and between sisters.1 There is also a correlation between age of onset and duration of puberty. Earlier the onset of puberty, longer the duration.8
The early onset of menarche in girls living in developed countries is thought to be due to improved nutritional status and healthier living conditions. It is argued that a critical body weight of somewhere around 47.8 kg must be reached by a girl in order to achieve menarche.9 More important than body weight is the shift in body composition to a greater percentage of fat (at least 20–25% fat) which in turn is influenced by the nutritional state.10 Indeed moderately obese girls have earlier menarche than girls with normal weight.11 Anorexia and intensive exercise are associated with delayed menarche or secondary amenorrhea. But the relationship is not completely straightforward. There are many other factors involved and this is indicated by delayed menarche experienced by morbidly obese girls (more than 30% overweight), diabetics and intensive exercisers of normal weight. Also blind girls experience earlier menarche.12 Further, it may be possible to hypothesize approximately that central mechanism brings about maturation of hypothalamo-pituitary-ovarian axis, which in turn stimulates growth to the critical weight, as well as increase in body fat composition.
Investigation of Delayed Puberty
History taking is very important to decide whether it is a case of primary or secondary amenorrhea. Frequently the parents would have taken a girl to several family doctors who are anxious to please and prescribe cyclical hormonal therapy over several months. This kind of administration frequently initiates growth of SSC thus creating a wrong impression in the mind of the clinician that one is really dealing with secondary amenorrhea. Many a time the girl gets married wishfully thinking that spontaneous onset of menses will ensue in due course. Unless the patient is taken into confidence and proper sympathetic attitude is shown to her, she may never reveal her real history. One should try and elicit the possibilities of cryptomenorrhea. This requires direct interrogation of patient for complaints of cyclical abdominal pain in the absence of cyclical bleeding. This may throw suspicion on retrograde menses and non-canalization of cervix and vagina. Special consideration has to be taken of general health, height, and weight records and the presence of pubertal milestones. History of older siblings and parents regarding their age at menarche must be noted. Interrogation about abnormal eating habits and excessive exercise for the purpose of slimming must be done.
While looking for SSC one must also look for signs of hypothyroidism, gonadal dysgenesis, hypopituitarism or chronic illness. Persistent deciduous teeth are typical of hypothyroidism. The failure of growth in stature suggests several possibilities. Isolated growth hormone deficiency is associated with somewhat delayed sexual maturity although menarche eventually occurs albeit delayed. Some types of gonadal dysgenesis, for example, Turner's with 45, XO will be associated with decreased height and sexual infantilism and this can be easily recognized clinically. Neurological examination is needed for evidence of intrapineal disease, restriction of visual fields, absence of smell, etc.
If the SSC are well-developed and the growth of the individual has been satisfactorily achieved, it means that the gonadal apparatus is functioning properly and the fault must be in the end organ or in the outflow tract. The most common condition associated with this situation is congenital absence of vagina and uterus. Examination of external genitalia must be carefully done. Presence of lush pubic hair, well-padded labia majora and minora add strength to the suspicion of absent vagina. Examination of introitus may show a normal looking vestibular mucosa, a proportionate clitoris and urethral meatus. On separating the labia majora and minora, the absence of hymenal orifice is sometimes difficult to diagnose unless an attempt is made to probe the hymen with a metallic instrument. This will give away the diagnosis. Rectal examination will elicit a band of fibrous tissue running horizontally connecting the 2 adnexa or one may even palpate a vestigial knob of uterus on either side. Frequently, the patient may become non-cooperative and visualization of introitus may become impossible. In such a case, examination under anesthesia becomes mandatory. An ultrasound examination of a full bladder will show absence of uterus and presence of well-developed active ovaries.
If a vagina is present and SSC are satisfactory, one must think in terms of a non-canalized cervix, although it is rare to see a well-developed vagina in the presence of an atretic cervix. All degrees of abnormalities of development of vagina have been noted. The author has seen the case of a girl brought up as a male till the age of 23, who had a history of passing altered blood through urethra periodically. She had concealed this from everyone including her parents. History was elicited on direct interrogation, when there was a good-sized uterus and functioning ovaries visible on ultrasound. The patient had a long clitoris which appeared like a rudimentary phallus. The phallus had a urethra and an external urethral meatus. Female SSC were entirely satisfactory. The patient had no scrotum but there was a midline raphe uniting the labia together. The lower end of vagina had opened into the urethra at a level where the urethra had taken a right angular turn from the level of perineum to form the penile urethra. The operation comprised of reduction of phallus, keeping the clitoris intact, cutting down on the midline raphe and opening into the tough skin which had closed the vagina. A well-formed vagina led to a healthy cervix. The patient menstruated satisfactorily, got married and produced 2 children eventually (Figs 1.3A to C).
All types of vaginal stenosis may be noticed like the presence of a transverse septum in the middle or upper one-third of vagina, or a septum just beneath the level of cervix and adherent to it. These conditions are usually associated with cyclical abdominal pain or the presence of menstrual fistula into bladder. Unsuccessful or half-hearted attempts to excise the bands will produce further scarring of the whole of vagina almost occluding it. The author has seen all the above varieties of vaginal atresia along with the iatrogenic complications thereof. Ultrasound examination of these patients may show a well-developed uterus and clear endometrial details. On occasions an endometrioma may be seen or either side of the ovary due to retrograde menstruation. Presence of hematometra may be seen during attacks of abdominal pain. On filling of bladder with fluid, one may see filling of the whole of vagina, also denoting the presence of fistula between the urethra or bladder and vagina.
Fig. 1.3A: Fully blown secondary sexual characters of a girl brought up as a male till 23 years of age
Fig. 1.3B: Fusion of labioscrotal fold with formation of a midline raphe and hypertrophy of clitoris
Classification of Primary Amenorrhea
Classification has been made in several ways by several authors. It may be classified according to:
- Status of gonadotropic activity: hypo, hyper or eugonadal state.
- Presence or absence of SSC and presence of heterosexual features.
- Chromosomally competent and incompetent state.
- The part played by each organ of the reproductive system causing amenorrhea, for example, hypothalamic, hypophyseal, gonadal, uterine and miscellaneous.
Whichever way one classifies primary amenorrhea, there will always be an overlapping of condition from one compartment to another. Since this book is meant for a practicing gynecologist, the features that are clinically evident are the SSC; so this system is used to start working out a diagnosis. The algorithm given below is reasonably helpful (Flow chart 1.1).
GROUP I: CONDITION WHERE SSC ARE WELL-DEVELOPED—CRYPTOMENORRHEA
Cryptomenorrhea of Acute Onset
This condition does not normally present as a case of delayed puberty. A girl of 13 to 14 years of age suddenly starts complaining of pain in the lower abdomen. The pain caused by collection of menstrual discharge in the vagina slowly disappears as the vagina accommodates 80 to 100 cc of menstrual blood. As this continues to recur every month, over a period of 3 to 6 months, the patient presents with severe abdominal pain with a mass in the lower abdomen rising from the pelvis. Retention of urine may also form a part of the picture due to compression of the urethra by the distended vagina. Examination of the perineum shows a tense bluish hymenal bulge. A catheter can be passed up the urethra and the retained urine can be released while the mass in the lower abdomen still persists. Diagnosis used to be very easy even before the era of ultrasound. But now with the help of ultrasound, a large cavity containing thick viscid material extending from the abdomen to perineum and on top of the swelling, the uterus may be noticed showing a normal endometrium or hematometra.
The immediate treatment is to incise the blue bulging membrane which is in fact an imperforate hymen. Blackish, tarry, viscous blood pours out continuously in a torrential manner so that nothing further can be made out. The perforation made by the sharp instrument can at best be widened digitally and the patient left alone to drain. The hymenal orifice tends to close quickly. Temptation to put a drain is to be avoided as this can cause easy passage of ascending infection. The drainage of menstrual blood can continue for 24 to 72 hours with fresh material pouring out each time as the hymenal orifice is digitally dilated.
After the draining stops completely, one must cut through the membrane around the orifice in a cruciate manner and trim the thickened edge all around. The raw edge can be oversewn in a circumferential manner to stop the bleeding. This secondary procedure is extremely important as otherwise the hymenal septum will close again and again.
Cryptomenorrhea of Chronic type
Transverse Vaginal Septum
A thick horizontal septum divides the vagina at any level into upper and lower segments. The septum is usually thick and does not bulge downwards unlike the appearance of an imperforate hymen. The lower segment of the vagina is usually patent and a finger can be pushed through the vaginal orifice until the septum is reached. Primary amenorrhea with cyclical abdominal pain is the chief complaint.
In a simple uncomplicated septum, mere excision of the septum and entering the upper segment, by carefully safeguarding the positions of the urethra and rectum, is all that is required.
Frequently one encounters a situation where the whole of the vagina above the septum is absent. Dissection has to be made in this space just as one does in Rokitansky' syndrome until the cervix is reached. The cervical external os is carefully occluded by a thick fibrous tissue. In such a situation, the operation has to be done in two stages. The transverse septum is opened up first and the edges trimmed off in a circular fashion. Digital dissection is made above the level of septum in the areolar space between the urethra and rectum until the cervix is reached. If this segment is short, a condom-covered teak wood mould is placed and one can expect the vaginal epithelium to grow upwards. If this segment is long, a skin graft has to be applied. (See details of operation for Rokitansky syndrome, under Rokitansky-Mayer-Huffner-Kauser syndrome heading).
The second stage of the operation is carried out after the vagina is fully epithelialized and stable. The cervix can be felt at the top of the newly formed vagina. This should be held by two pairs of long Allis forceps and pulled down to the middle of the vagina. At this stage the use of an abdominal ultrasound to guide the position of the bladder and the direction of cervical canal will be of immense help. The external os may have to be penetrated by the use of a pair of curved, narrow-bladed scissors. If the operation is done at the time of menses, a hematometra is usually visible. As the dilator is pushed through the internal os into the uterine cavity, dark menstrual blood starts pouring out. From now on, dilatation of the cervix can be easily done up to 8 or 9 mm. Tendency to restenosis of the cervical os should be prevented by stitching the vaginal skin to overlap the raw edge of the cervix all round, just as one does during the course of Fothergill's operation.
The patient usually menstruates once or twice per vagina but later the cervix shows a tendency of stricture-formation again. Dilatation of cervix may again have to be done on one or two occasions.
The surgeon who handles the case first must design the steps of operation and carefully proceed with it to reach completion. Incomplete handling and abandoning the case after one or two half-hearted attempts can complicate the situation immensely. The author has seen such cases with various levels of obstruction. A previous handled case showed scar tissue occluding the whole of the vagina from about one inch from the introitus till the cervix. There was a narrow devious track in the midst of a scar tissue which was allowing a trickle of menstrual blood during each month while the patient complained of severe cramping. The operation consisted of probing the tract within the scar tissue which had pulled the urethra towards the vagina. The tract was repeatedly dilated using blunt and sharp instruments step-by-step over several months. After each dilatation a teak wood mould covered by a condom was placed as an indwelling stent. The size, thickness and length of moulds was increased during every procedure and the vagina became longer and longer and the lumen wider. As this happened the vaginal mucosa grew upwards all round. The tendency to restenosis was discouraged by continued use of the vaginal mould. This was done over several months till the cervix was reached. The vagina eventually became normal reaching the correct length and width. Menstruation was satisfactory and dysmenorrhea disappeared. The patient abandoned the use of mould only after marriage. This kind of situation requires a lot of patience and perseverance both by the surgeon and the patient.
GROUP I: SSC PRESENT—TRUE AMENORRHEA
Primary Amenorrhea due to Physiological Delay
This is found in about 10% cases of delayed puberty and it is frequently familial. The most common form is that of a girl in her mid or late teens who has suggestion of onset of puberty but has still not started menstruating. Gonadotropic hormone levels may be almost normal or marginally reduced with FSH levels always higher than LH at this stage. A normal vagina and a normal uterus can be ascertained by clinical examination. With the use of ultrasound application, appearance of multicystic pattern of ovaries can be seen and this would give an assurance that menarche is not far away. In a series of 9 patients collected by Rodney Shearman, all of them menstruated spontaneously by the age of 21.13
Amenorrhea Related to Weight Loss
This condition is said to be caused by hypothalamic reaction to weight loss. The association of weight loss to amenorrhea is usually seen in women who have had normal menarche originally and complain of secondary amenorrhea; but this condition can also occur in children and may present as primary amenorrhea at pubertal age. It is usually related to children undergoing rigorous exercise and weight-reducing-diet in order to become eligible for careers like dancing, modeling, gymnastics, athletics, etc. Patients look well, feel well; they are ambitious, belonging to the upper class societies and are often over-achievers. They show normal or low gonadotrophin levels. The fault lies in the absence of pulsatile release of GnRH from the hypothalamus.14 Wentz has shown that loss of 40% body mass is sufficient to induce menstrual dysfunction.14 This kind of amenorrhea is associated with hypogonadotropic hypogonadism.
Primary Amenorrhea due to Total Absence of Vagina (Rokitansky-Mayer-Huffner-Kauser Syndrome)
Mayer-Rokitansky syndrome (MRS) are cases of primary amenorrhea in women with total development of SSC and an entirely normal looking external genitalia. In this fairly common condition, superficial examination shows a normal looking hymenal membrane situated at about the upper end of the vestibule, 1–1.5 cm from the surface. Cursory examination gives an impression that this would lead to a normal vagina; but on digital probing it shows that it ends blindly. Internal genitalia consist of well formed tubes which lead to a normal looking ovary on either side. The uterus is often represented by a muscular knob on either side, the knobs being connected to each other by a thin horizontal flap of membrane which may show a fibrous thickening. About 40% of these patients are said to have various types of renal anomalies including an absent kidney.
Mayer-Rokitansky syndrome (MRS) consists of absence of vagina with other müllerian duct abnormalities. In this syndrome, the external genitalia looks entirely normal and the mother may not be able to suspect the absence of vagina till about the age of puberty. The incidence of this syndrome is 1/4000 to 5000 female births and it is also said to be second most common cause of primary amenorrhea. The condition becomes detected only when the young girl does not get her menarche at the expected time. Her SSC develop normally and for all practical purpose she has undergone puberty with normal thelarche (breast development) and adrenarche. This is because her ovarian function is normal, and the patient develops all other changes in the body associated with puberty.
Externally the labia majora, the labia minora and vestibular mucosa appear entirely normal. One can also see the garland of papillae starting from below the level of urethra and reaching as high as 1/2″ from the fourchette. Unless one looks for the presence or absence of hymenal orifice with a blunt instrument or an index finger, one may not recognize the absence of vagina. Same can be confirmed by placing a finger into the rectum and pushing the anterior rectal wall downwards to reach the hymenal region.
The absence of cyclical abdominal pain discovered only by direct interrogation, shows that the patient has no functioning uterus either. The degree of vaginal aplasia may vary from complete absence to a shallow pouch in the vestibular region.
Laparoscopic examination in such women usually shows a well developed tube and a good functioning ovary on either side. The uterine vestige is frequently seen of the size of marble at the medial end of each tube. A horizontal fibrous band or fold of peritoneum may be seen running between two vestigial uterine mass. The ovarian function is preserved because the ovaries originate from primitive ectoderm unlike the uterus, cervix and upper two-thirds of vagina which normally fuse to form a single uterus, cervix and upper vagina.
The vestibular portion of vagina fuses with mullerian contribution of vagina at the level of hymen. When the two contributions of vagina fuse together completely, the hymenal orifice comes into existence.
MRS has psychological consequence – by appropriate treatment, normal sexual function can become possible. In the absence of uterus, she can still contribute her ova and organize a surrogate conception. But before one undertakes any of the surgical intervention to allow the patient to have a normal sexual function, the patient must be counseled thoroughly that she will never be able to menstruate or conceive her own baby.
A gene responsible for MRS has not been identified. It is generally a sporadic condition and as a rule, it has not been transferred to her off spring even if she contributes her ova for surrogate conception. In doubtful cases, one may want to exclude karyotying abnormalities for Turner's syndrome (XO) and Androgen Insensitivity Syndrome (XY).
RE-CONSTRUCTION OF VAGINA
Several methods of surgical treatments have been described. Whichever method is taken up, it requires proper counseling of the patient and a commitment to succeed in the procedure, both in the mind of patient and the surgeon.
Archibald Mcindoe's Operation
A close inspection of external genitalia shows the presence of a series of small papillae placed in elliptical fashion from the lower margin of external urethral meatus and running along the hymenal membrane demarcating the area where the hymenal orifice should have been present (Fig. 1.4A).
This area surrounded by a garland of papillae can be recognized in all patients and the central point of this area is closer to the urethral orifice than that of the anus. If an incision is made in the middle of this area, one gets straight into the areolar space between the urethra and rectum. Sharp dissection is required only at the lower end for about 2 - 2.5 cm both laterally and upwards (Figs 1.4B to E).
From then on, digital dissection is all that is necessary. A Foley's catheter is inserted into the urethra and a large metallic dilator is placed temporarily in the rectum for the purpose of guidance during upward dissection. The dissection is carried out until the peritoneum is reached. This can be done within a span of 5 to 10 minutes. Small bleeders sometimes appear and these can be coagulated by bipolar cautery.
The space created may be about 12 to 15 cm in length and the diameter as wide as required and as distendable as a natural vagina. This space is temporarily plugged with a ribbon gauge for the purpose of homeostasis while the mould is being prepared by a plastic surgeon.
Preparation of Vaginal Mould
The vaginal mould is made out of a roll of rubber foam sponge which is made into a cylindrical form of the size of about 10 cm in length and 5 to 6 cm in diameter. A red rubber catheter is placed in the middle of the mould all the way. The mould is now pushed into a sterile rubber condom and the distal end of the condom is tied onto the red rubber catheter. A split skin graft is taken from the medial aspect of the patient's thigh. The length and width of the graft should be enough to cover the entire mould. The mould is now wrapped over by a thin layer of vaseline tullegras. The skin graft is then wrapped over the mould with the raw area upwards and the smooth area towards the mould.
The ribbon gauze plug in the vaginal space is now removed and the space is again inspected to ensure that there is no bleeder. The mould is now slipped into the space created.
Insertion of the mould can be made easy by connecting the indwelling rubber catheter to an electric sucker.
Fig. 1.4A: Left: Incorrect incision too far behind the topography of “hymenal orifice”. Right: Correct incision – passing through the middle of “hymenal orifice”
The electric suction sucks away the air trapped in the rubber mould. The mould temporarily shrinks to less than half its size and the insertion becomes very easy. Once the mould is placed in the vagina, the sucker is removed with immediate return of air into the mould. The mould again gets enlarged and now fits snugly into the space. The mould is kept in space by closing the labia majora temporarily. A pressure bandage is also applied over the perineum. The Foley's catheter is connected to a bottle for continuous drainage. The red rubber catheter is left inserted in the mould for using the same technique of reducing the size of the mould while taking it out 5 to 6 days later. Postoperatively the patient takes a low residue diet. It is preferable that she does not pass motion for at least 4 days. On the 5th day the labial stitches are removed and the vaginal mould is gently eased off the space once again by sucking air from inside the spongy mould. One will see that the skin graft takes over a major portion of the space. Excess skin tissue peels off the space and this may be removed by a gentle wash with sterile saline. The patient is now ready for the application of a teak wood mould covered over by a sterile condom about 9 cm in length and 4 cm in width, in the newly formed vagina. A sanitary towel is tightly placed in order to keep it in place. The patient may be discharged after about another 3 to 4 days when the catheter will be removed and she passes urine by herself.
Postoperative follow-up consists of the patient attending as an outpatient for taking out the mould and periodical inspection of the vagina. Sloughing of excess skin graft may be seen and this may have to be removed. The teak wood mould is covered with a sterile condom and a greasy antibiotic cream is applied over the condom and also applied into the vagina and kept in place by a sanitary towel. The epithelialization of vaginal space is usually complete in about 15 days by which time the donor area of the thigh would have also healed. The patient is now asked to change her mould daily by herself. She is advised to use it throughout the day for 2 to 3 months in the beginning and later on she may use it only at night. The mould can be completely discarded once she gets married and satisfactory sexual activity is started.
This is a highly satisfactory operation provided the surgical principles are correctly practiced. Inadvertent entry into the rectum during the time of dissection will result in total operation failure. One must remember that the first surgeon always has the best chances of getting best results and subsequent surgeons quite often end up repeating the same mistakes as done by the first surgeon.
This operation is conducted by making a vulval flap to make a vaginal tube ignoring the normal situation of vagina. The operation is simple. There is no fear of damaging the urethra or rectum. The dilatation is needed for a lengthy period for maintenance. Moreover, the axis of neovagina is more or less at right angle to that of the normal vagina and this may not be acceptable to the male partner.
Frank Technique or Perineal Dilation
This technique is possible in patients with a long rudimentary vagina. Such patients can be given stents or blunt wooden dilators of gradually increasing diameter and length. These can be used inside a condom, applied into the vagina and held in place by a pressure bandage or sanitary napkin. The length of the dilators must be such that, patient should not experience any discomfort. Change of size of stent or a dilator must be increased very gradually. This may take 6 months to 1-year and once the necessary dilatation has occurred, the patient must be asked to apply only in the night and maintain the lumen until she becomes sexually active.
On rare occasions where a functioning uterine mass is also present in midline attached to tubes on either side, concealed menstruation can produce hematometra, cyclical abdominal pain and endometriosis. A uterus of this type is occasionally seen associated with partial or total aplasia of vagina. The globular uterus itself does not show any cervix. A horizontal incision can be made at the lower end of globe and brought down to the level of the new vaginal vault explored, discovered or constructed and anastomosis may be carried out. This has been attempted on few patients as a second stage procedure after vagina has been found to be well reinforced, but so far they have all ended in the uterus springing off from the vaginal vault and setting itself free after one or two successful menstrual drainage per vagina, finally resulting in reappearance of cyclical abdominal pain.
Amenorrhea due to End Organ Failure
This endocrine order is one of normogonadotropic normogonadism where the HT-HP axis is functioning normally, but the patient does not menstruate. Administration of estrogen and progesterone therapy does not produce withdrawal bleeding because there is total absence or destruction of endometrium. Absence of endometrial receptors to gonadal hormones is an almost unknown phenomenon. However, destruction of the endometrium can occur due to tuberculosis and this is fairly common in our country. Once the basal layer of endometrium is destroyed, no hormone treatment will help these cases.
GROUP II: INVESTIGATION AND MANAGEMENT OF PATIENTS WITH PA ASSOCIATED WITH ABSENCE OF OR POORLY DEVELOPED SSC
These cases may be associated with hypogonadotropic hypogonadism or hypergonadotropic hypogonadism. Hence, it is extremely important to get a gonadotropic hormone assay. This will give an idea whether the fault is at the HT/HP level (hypogonadotropic pathology) or if it is at the level of the ovary (hypergonadotropic situation).
Hypogonadotropic hypogonadism may be due to several conditions like physiological delay, weight loss and anorexia-related hypogonadotrophism and excessive exercise. This condition is already dealt with in Group I.
Poor nutrition due to poverty, malabsorption, and chronic illnesses like tuberculosis and renal disease lead to hypogonadotropic delayed growth and development. History of drug abuse, particularly marijuana, must be sought for.
Tumors arising from the hypothalamic region and growing downwards and those arising from the pituitary gland growing along the suprasellar direction can obstruct the flow of hormones coming from the hypothalamic direction. For example, GnRH, dopamine, etc. are prevented from reaching the pituitary gland, thus causing secondary hypogonadotrophism, due to non-availability of these molecules. Non-availability of dopamine can result in hypotrophy of lactotrophs in the pituitary gland. Pituitary microadenoma and macroadenoma can also cause amenorrhea. Other space occupying lesions in the pituitary gland can compress upon the gonadotropin producing tissues and can result in primary hypogonadotrophism from the pituitary. A cat scan or MRI along with examination of visual fields by the ophthalmologist is mandatory in these conditions (For further details of Hyperprolactinemia).
Hypogonadotropic hypogonadism may be of a congenital etiology as an isolated GnRH deficiency with or without loss of olfactory sense.
Isolated GnRH Deficiency
In this condition the hypothalamus lacks the ability to produce Gonadotropin Releasing Hormone (GnRH) resulting in a hypogonadotropic state. If the patient also suffers from anosmia, the condition is known as olfactogenital syndrome or Kallmann's syndrome. This condition may occur sporadically, or as a gene deletion recurring familially. The patient presents with primary amenorrhea and sexual infantilism with variable height.
The serum levels of FSH and LH can be brought to normal by pulsatile infusion of GnRH indicating that the pituitary gland beneath the HT is potentially normal. Exogenous administration of gonadotropins will stimulate ovarian activity and cause hypertrophy of uterine myometrium and endometrium. The levels of estrogen can be assessed, follicular recruitment can be studied by ultrasound and ovulation may be induced by injection of Human Chorionic Gonadotrophin (hCG).
Management of Hypogonadotropic Amenorrhea with Absence of SSC
Once the diagnosis is made and cause of amenorrhea understood, the management is aimed at bringing about complete development of SSC. This is done by starting off with small doses of estrogens, either equine or natural estrogen in the form of estradiol (See treatment of Turner's syndrome). It is very important to know whether the patient still has a growth potential. If the growth limit has not yet been reached, sudden administration of large quantities of estrogens can result in fusion of epiphysis. One should therefore start the patient with small doses and build up heavier doses by the end of 12 to 18 months. One must try to produce a gradual development of external genitalia and SSC; and at the same time encourage growth of the skeleton. At the end of 2 years as the treatment is coming to a plateau, the patient may be given estrogen-progesterone hormones in a cyclical fashion so that she menstruates at regular intervals.
The ovaries of hypogonadotropic women can be stimulated by administering gonadotropic hormones, but this has to be postponed till the patient gets married and expresses her desire to conceive. Till then cyclical E2-P therapy will be adequate. Usually such patients require massive doses of gonadotropic hormones to stimulate their ovaries, but when they respond they produce a large number of follicles with multiple ova. Danger of OHSS and high degree of multiple pregnancies might occur. After delivery and lactation, they will go back to the hypogonadal state. Cyclical hormone therapy will have to be restarted in order to maintain the SSC, vaginal lumen and prevent osteoporosis.
Hypergonadotropic hypogonadal state always means that it is a case of primary ovarian failure. The HT and HP are overfunctioning because of the absence of production of estrogen and progesterone from the gonads. In this situation it is important to diagnose the cause of ovarian failure. The possibilities are:
- Absence of ovaries or presence of streak gonads (Turner's syndrome—pure or Mosaic)—Karyotype 45, XO or 45, XO/46, XX or 45, XO/46, XY.
- Resistant ovarian syndrome (XX)
- Ovaries destroyed by autoimmune phenomenon.
- Premature exhaustion of ovarian follicles due to deletion of genes from the p or q arms of one of the X chromosomes.
- Insufficiency of ovarian receptors to gonadotropic hormones.
- Androgen insensitivity syndrome also called Testicular Feminizing Syndrome. The hypoplastic male gonads are concealed either in the abdomen or in the inguinal canal - Karyotype 46, XY.
Turner's or Turner's mosaic: In this condition the gland that has failed primarily is the ovary. Gonads may be totally absent or may be represented by fibrous tissue only (streak gonads) mixed with or without stromal tissue. There are no primordial follicles. In true Turner's syndrome, which is a condition of gonadal dysgenesis, the karyotype is 45, XO. There may be Turner's mosaic where a mixture of two cell lines, 45, XO and 46, XX chromosomes are present. These patients may show development of SSC to a lesser or greater extent depending on the dominance of 45, XO or 46, XX. There is another chromosomally competent group that has a chromosomal typing of 46 XX only. These have a few deletions in the p or q arm of the X chromosome. The loss of genetic material in the individual hampers the development of reproductive system.
On physical examination of women with PA, a true Turner shows total absence of SSC. The patient is typically short and has poorly developed nipples and areola spaced far apart. Other stigmata of this syndrome are webbing of the neck, pectus cavum and congenital heart disease like coarctation of aorta. It must be noted that every short individual with evidence of infantilism and webbed neck need not be a case of Turner's syndrome. It must also be remembered that every individual with XO or XO mosaic need not have all features of Turner's phenotype. The development of SSC may vary from person to person from non-development to partial development or almost complete development on occasions.15
In a fetus with Turner's syndrome, ovarian development is normal until 20 weeks of gestation and oocytes are formed in the ovaries at this stage. Thereafter there is failure of oocytes to undergo further maturation which requires the influence of both X chromosomes; so the oocytes begin to undergo the process of atresia which probably continues beyond birth until puberty in some individuals. The ovaries in most individuals at this stage consist solely of stroma and therefore are unable to produce estrogen. Internal genitalia are of normal female type as the absence of Y chromosome leads to development of uterus, tubes and vagina. The loss of the second X chromosome is associated with short stature as the determinant genes for height are lost.
In Turner's mosaic, the proportion of each cell line determines the manifestation of the condition. Thus, the higher the percentage of 45, XO cells, the more typical are the features of Turner's. With the presence of a larger number of normal 46, XX cell lines, there is a possibility of ovarian differentiation and associated development of SSC. About 10 to 15% of girls exhibit some estrogenic activity and a few have conceived also.16
Another group of disorders should be mentioned just to be kept in mind. In children who have hydrocephalus at birth, it is presumed that the hypothalamus also gets damaged leading to hypothalamic amenorrhea. Similarly trauma resulting in severe head injuries may cause injury to hypothalamus and cause PA. Intrapineal neoplasms must always be considered in patients with PA. Pituitary tumors such as craniopharyngioma which interferes with the blood flow from hypothalamus to pituitary gland may also act primarily through destruction of pituitary gland itself. All these have to be investigated in cases where more common etiological factors have been excluded.
Laparoscopy and ovarian biopsy are not required in pure Turner's syndrome but may be necessary in Turner's mosaic with a mixed configuration of 45, XO and 46, XY. The gonadal biopsy may show the presence of testicular morphology and in such a case the gonads have to be excised. Treatment of Turner's syndrome is based on psychological support, proper counseling of the patient and her parents and institution of HRT. The goal is to help the development of SSC without compromising skeletal growth. Cyclical menstruation must be eventually achieved so as to give self-confidence and self-esteem to the patient. Treatment should be started with small doses of ethinyl estradiol 1–2 ug/day or equine estrogen (Premarin) 0.3mg/day which can be gradually increased to 20–30 ug/day or 3.75 mg/day respectively. The aim is to mimic natural puberty after the full dose of estrogen is achieved when complete developments of SSC have appeared. Progesterone should be added for 10 days every 4 weeks to prevent the problem of unopposed estrogen on the uterine lining. Some individuals may continue to have stunted growth. Individuals with Turner's syndrome can live a full life as a young girl, woman and wife. But since the ovaries are completely devoid of primordial follicles, they can never ovulate. Such patients can be treated with oocyte donation and pregnancy carried to term.
There are instances of Turner mosaics—45, XO/46, XX—ovulating sporadically and even conceiving spontaneously.15
Hypergonadotrophic amenorrhea with normal 46, XX karyotype. This condition is much more common than Turner's syndrome. These women undergo premature ovarian failure. The causes may be: (i) Absence of valuable genes in the p or q arm of one of the X chromosomes, (ii) Absence of receptors for GTH in the ovarian follicles, (iii) Absence of ovarian follicles due to disruption by: (a) autoimmune phenomena, (b) total body irradiation along with chemotherapy given together in young children or (iv) Surgical castration for various diseases.
Management of Hypergonadotropic Amenorrhea with 46, XX Karyotype
The SSC are absent if the ovarian failure occurs in prepubertal stage. Lack of ovarian estrogen results in increased functioning of HT and HP. The preliminary treatment is given on the same principles as in Turner's syndrome. The initial treatment is aimed at developing SSC whether they are having hypo- or hypergonadotropic profile.
Hyper- or normogonadotropic amenorrhea in 46, XY karyotype individuals with or without SSC. Also known as androgen insensitivity syndrome or testicular feminization syndrome, is a form of gonadal dysgenesis occurring in chromosomally normal males. During male embryonic development, there is an enzymatic failure because of which androgen production is inhibited. Clinical features will depend on the time of testicular failure in fetal life; (i) whether the testis never developed at all, or (ii) has failed after mullerian inhibition had become effective or (iii) after the 20th week of pregnancy when complete masculinization had occurred.
In situation (i) the testes fail to develop. The müllerian suppressor factor of Sertoli cells is not forthcoming; hence the müllerian ducts are not suppressed. They develop into fallopian tubes, uterus and upper vagina. The cloaca may also assume a feminine form and clinical presentation of this individual will then be one of PA with sexual infantilism. This can only be distinguished from true gonadal agenesis by karyotyping.
In situation (ii) the müllerian components have been almost completely inhibited perhaps allowing only a segment of vagina to grow. The uterus and tubes are absent. The external genitalia look like that of a female. Androgens produced in small quantities by the gonad are converted to estriol by the peripheral skin and fatty tissue. This frequently stimulates the formation of breast hypertrophy. A normal adrenarche may also produce growth of axillary and pubic hair in some individuals. When adrenarche and thelarche appear, the unsuspecting family will be waiting for the pubertal changes to culminate in menses which never arrives since there is no uterus in this individual. Since there is no estradiol produced, and the amount of androgen produced is minimal, the patients usually have a hypergonadotropic state. The degree of formation of internal genitalia may also be varied in different individuals. Some individuals may only have a short vagina of about 3 to 4 cm and total absence of uterus and tubes. This again shows the difference between this condition and Rokitansky's syndrome wherein the tubes and ovaries are very well developed.
In the third subgroup of this kind of individuals, there is mid-fetal failure of testicular organization. müllerian duct inhibition might occur but wolffian duct components develop partially. The gonads may remain in the abdomen and scrotum may be empty and bifid. The clitoris may hypertrophy assuming the shape of a miniature phallus and the urethra may run into it causing various types of hypospadias. The patients may not present as a case of PA. They may appear even earlier as ambiguous genitalia.
Management of Androgen Insensitivity Syndrome
Women with androgen insensitivity syndrome may have testis concealed in the abdomen. These have to be removed laparoscopically in order to prevent future possibility of malignancy.
A short vagina has to be lengthened by regular digital dilatation. A mould may have to be kept in the vagina to prevent restenosis. The width and length of the mould should be periodically increased so as to stretch the vagina deeper and deeper. Only rarely one may have to do a partial or full operation by skin graft as described in the treatment of Rokitansky's syndrome. The intra-abdominal position of the male gonad causes the risk of malignant transformation and these have to be removed and can be easily done so laparoscopically. HRT has to be commenced gradually. If SSC have not completely appeared and growth potential not completely reached, the principle of therapy is same as in Turner's syndrome. Since in most cases the uterus is absent and if at all it is present, the uterus is very rudimentary, it is not possible to expect menses to appear even after HRT. Therapy has to be given to prevent osteoporosis and early onset of arterial disease. Since the uterus is absent, estrogen therapy alone would be sufficient and there is no need to give additional progesterone.
GROUP III: PA WITH HETEROSEXUAL DEVELOPMENT OF SSC
This group consists of: (i) puberty onset congenital adrenal hyperplasia, (ii) androgen secreting tumors of the adrenal gland, (iii) partial androgen receptor deficiency may also show similar features as those belonging to this syndrome.
Congenital Adrenal Hyperplasia (CAH)
This condition presents at birth posing difficulty in gender allotment but if this does not happen, the problem may start at puberty with clitoral enlargement. It is an autosomal disorder leading to enzyme deficiency in the synthesis of cortisol, the most common being 21-hydroxylase deficiency. Mutation of two genes situated in the short arm of chromosome 6 are said to be responsible for this pathology. Deficiency of 21-hydroxylase leads to failure to produce cortisol in normal quantities which in turn leads to increased production of ACTH and increased production of cortisol precursor 17-L hydroxy progesterone which gets converted to androgens. This elevated level of circulating androgen leads to varying degrees of masculinization. The vagina is always present. Internal genitalia are normal but external genitalia may vary from fused labia to severe stenosis of the lower two thirds of the vagina with an associated urogenital fistula.
Pubertal enlargement of clitoris may be the first sign of elevated levels of androgen. The clinician must look for other androgenic tumors arising from the ovary and pituitary gland. MRI, cat scan and ultrasound examination may be judiciously used if such tumors are suspected. On the other hand, estimation of serum 17-L hydroxyprogesterone and ACTH will give the diagnosis of CAH. The adrenal gland may show an enlargement of 4–5 times the normal (the largest gland reported in this discussion was 90 gm as compared to a normal weight of 5 gm).17
Failure of treatment in early childhood results in increased amount of steroid which may cause increased growth and later premature fusion of epiphysis resulting in considerable stunting of growth. Treatment consists of administration of cortisol in appropriate doses in consultation with a good endocrinologist. Some reconstruction of external genitalia will be required such as clitoral reduction, division of fused labia and closure of urogenital fistula, etc.
Other hormone producing tumors of the ovary are not dealt with in this chapter.
Investigations for primary amenorrhea may be started if a well-nourished young girl has not developed SSC by the age of 15 or having developed the SSC, has failed to achieve menarche by the age of 16. Family history of delayed menarche and ultrasound appearance of multicystic ovaries are reassuring features for delaying investigation.
Imperforate hymen does not really present as primary amenorrhea. Such girls present with a history of severe abdominal pain and difficulty in micturition and mass in the abdomen around the age of 13 or 14.
Women with transverse septum in the vagina and a functioning uterus may present as primary amenorrhea, but they complain of cyclical abdominal pain. These patients should be operated without delay since it can lead to irreversible tubal damage, ovarian adhesion and pelvic endometriosis.
Congenital absence of vagina is almost invariably associated with either total absence of uterus or presence of rudimentary, non-functioning uterus. Operation consists of creating a vagina artificially. This would give eminently satisfactory sexual function. Patients however, must be counseled before hand that menstrual function and reproductive potential can never be achieved.
When SSC are absent, one must proceed to estimate the levels of gonadotrophic hormones. If they are low, it may be due to primary hypothalamic or hypophyseal deficiency. Tumors in and around the pituitary fossa should be ruled out before starting treatment. The patient has to be treated with oral estrogen therapy starting from low doses and increasing gradually over a period of one to two years. After SSC are developed and growth peak is achieved, one must add progesterone therapy cyclically and produce withdrawal bleeding. Gonadotropic therapy should be given only when the patient gets married and desires to conceive. The estrogen-progesterone therapy is given for life.
Hypergonadotropic women should have their karyotype done. They could be normal 46, XX in which case they may be having deletion of genes in the p or q arms. They may be pure or mosaic Turner's or they may be 46, XY with androgen resistance syndrome. Except for an occasional Turner – mosaic, none of them will conceive spontaneously. The initial treatment regime should be same as that given to hypogonadotropic women. But there is no way of stimulating their ovaries since the ovaries are completely devoid of primordial follicles. If the uterus is present and cyclical withdrawal bleeding is satisfactory with E2 and P then these women can be informed that pregnancy is possible with donated ova. Women of 46, XY karyotype, with androgen insensitivity syndrome, should have their ectopic gonads removed in order to prevent malignant changes.
Women with pubertal onset of virilization are likely to be cases of congenital adrenal hyperplasia with 17-hydroxylase deficiency. Investigation must also be made to look for androgen producing tumors of the ovary, adrenal or pituitary gland. When these are ruled out, they should be put on cortisone therapy for life. These women, if treated properly, can have full restoration of reproductive function.
In women who have normal anatomy of internal and external genitalia and who also have normal gonadotropic normogonadal hormone profile, atresia of uterine cavity caused by chronic diseases like tuberculosis must be suspected. They do not respond to exogenous E2-P therapy. If there is no active disease that originally caused the atresia, no other treatment is indicated. They will continue to be amenorrheic and will also remain sterile.
No hormone therapy should be started without making a complete diagnosis and without making a purposeful therapeutic plan for life. Laparoscopy for examination of internal genitalia, chromosomal assay, advanced radiological investigations like CT scan, MRI and gonadal biopsy, etc. have very limited value. These may be done for the purpose of academic interest or when indicated absolutely for the purpose of planning of therapy.
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