Tempo of pubertal development

Although the endocrine changes during puberty have become better understood, the exact ‘trigger’ which determines the onset of pulsatile GnRH release, and thus the initiation of puberty, is still unclear. The question of which factors might regulate the onset of puberty and control the rate of pubertal development has prompted extensive research. The majority of studies examining young women have used age at menarche as the key marker of sexual maturity, and have attempted to elucidate which factors are involved in the timing of this event.

The first physical sign of puberty in girls is breast development, which occurs at an average age of 10–12.5 years (Figure 14.2). Age at onset of puberty is influenced by family history, race (earlier in Afro-Caribbeans) and nutrition (earlier in obese girls, with a secular trend to younger ages). Fifty percent of girls show signs of breast development by the age of 11 years, and investigations should be performed if there is no sign of breast development by the age of 14 years. In girls, the adolescent growth spurt occurs around 1 year after pubertal onset, while menarche occurs in the later stages of puberty at an average age of 12–15 years, at breast and pubic hair stage 4 (Figures 14.3 and 14.4; Marshall and Tanner 1969). Oestradiol concentration affects both the uterus and skeletal maturity. Most girls begin to menstruate when their bone age is between 13 and 14 years, and fewer than 20% are outside these limits. The appearance of axillary hair may antedate the rest of puberty by a few years and does not bear a constant relationship to the development of breasts as, again, it is androgens and not oestrogens that are most significant. The apocrine glands of the axilla and vulva begin to function at the time when axillary and pubic hair is appearing.

Figure 14.2 Stages of breast development at puberty. Stage 1: the infantile stage, which persists from the time the effect of maternal oestrogen on the breasts disappears, shortly after birth, until the pubertal changes begin. Stage 2: the bud stage. The breasts and papillae are elevated as a small mound and there is an increase in the diameter of the areola. This stage represents the first indication of pubertal change in the breast. Stage 3: the breasts and areola are further enlarged to create an appearance similar to that of a small adult breast, with a continuous rounded contour. Stage 4: the areola and papilla enlarge further to form a secondary mound projecting above the contour of the remainder of the breast. Stage 5: the typical adult breast with a smooth rounded contour. The secondary mound present in stage 4 has disappeared.

Figure 14.3 Stages of pubic hair development at puberty. Stage 2: sparse growth of slightly pigmented hairs on either the labia or the mons pubis. Stage 3: the hair is darker and coarser, and spreads sparsely over and on either side of the midline of the mons pubis. Stage 4: the hair is adult in character but covers a smaller area than in most adults and has not spread to the medial surface of the thighs. Stage 5: hair distributed as an inverse triangle and spreading to the medial surfaces of the thighs. It does not spread to the linea alba or elsewhere above the base of the triangle.

Figure 14.4 Timing of pubic hair and breast changes and menarche. Horizontal line represents mean ± 2 standard deviations.

It has long been recognized that early maturing women have a tendency to be heavier for their height than their later maturing counterparts and, in contrast, that malnutrition and anorexia nervosa are associated with delayed menarche and amenorrhoea. These observed relationships between body weight and menarche led to the ‘critical weight hypothesis’ of Frisch and Revelle (1970), which hypothesized that attainment of a critical body weight led to metabolic changes which, in turn, triggered menarche. In further work, the investigators demonstrated that the ratio of lean body weight to fat decreased during the adolescent growth spurt in females from 5 : 1 to 3 : 1 at menarche, when the proportion of body fat was approximately 22% (Frisch 1990). They suggested that adipose tissue specifically was responsible for the development and maintenance of reproductive function, through its action as an extragonadal site for the conversion of androgens to oestrogens.

While few authors will dispute that nutrition and body weight play a role in pubertal development, the ‘critical weight hypothesis’ for menarche has not been supported by other studies. Cameron (1976) studied 36 British girls longitudinally, measuring weight and skinfold thickness at 3-month intervals for the 2 years before menarche to 2 years post menarche. He postulated that if a ‘critical body fatness’ was the true explanation for onset of menarche, he should expect to detect a reduction in the variability of his measurements at menarche compared with measurements taken before and after menarche, and this was not demonstrated in the study. In a much larger study, Garn et al (1983) analysed the triceps skinfold distributions of 2251 girls collected during three national surveys in the USA. Comparing premenarcheal and postmenarcheal girls, they confirmed that those who had attained menarche were, on average, fatter than premenarcheal girls. However, there was a marked overlap in skinfold thickness for both groups, and there was no evidence of a threshold level of fatness below which menarche did not occur. In a more recent study, de Ridder et al (1992) performed a longitudinal assessment of 68 premenarcheal school girls, including pubertal staging, skinfold measurements, waist–hip ratios and blood samples for the monitoring of gonadotrophins. They did not demonstrate a relationship between body fat mass and the age at onset of puberty or age at menarche, but did find that a greater body fat mass was related to a faster rate of pubertal development.

Although the studies above dispute the association of age at menarche with the achievement of a threshold weight or body fat percentage, the association of earlier maturation in heavier girls still exists. Stark et al (1989) reported on data from 4427 girls who were part of the National Child Development Study cohort. Data relating to birth weight, age at menarche, and weights and heights measured at 7, 11 and 16 years were available. The authors reported that a larger proportion of girls with early menarche (before the age of 11 years) were heavier for their height at all ages when compared with those with late menarche (after 14 years). Interestingly, however, changes in relative weight in the years preceding menarche (ages 7–11 years) were not strongly associated with age at menarche, whereas being overweight at the age of 7 years was much more strongly associated with an early age at menarche. Birth weight was not related to age at menarche. The authors concluded that the increase in weight for height associated with early maturation actually begins well before the onset of puberty. These findings were replicated by Cooper et al (1996) who examined 1471 girls in the Medical Research Council National Survey of Health and Development. They found that girls who were heavier at 7 years of age experienced an earlier menarche; however, contrary to Stark et al, they found that birth weight was related to age at menarche and that girls with heavier birth weights experienced menarche at a later age.

Intense exercise, such as long-distance running, ballet, rowing, long-distance cycling and gymnastics, is associated with delayed menarche in young girls and with amenorrhoea in older women (Malina et al 1978, 1979, Frisch et al 1981, Baxter-Jones et al 1994). These ‘endurance’ sports are associated with lower body weight and percentage fat. The extent to which menarche is ‘delayed’ has been shown to be related to the age at which participation in the sport begins and to the intensity of training (Frisch et al 1981). In view of the association between body weight and menarche described above, it is perhaps not surprising that girls participating in intense sporting activity experience a later age of menarche.

The influence of genetic factors on age at menarche is evident in the correlation demonstrated between mother–daughter and sister–sister pairs. Garn and Bailey (1978) analysed data from 550 mother–daughter pairs and reported a correlation of 0.25, which was adjusted to 0.23 once a correction was made for fatness. Similar correlation coefficients have been reported in other studies of mother–daughter pairs from European, African and American populations (Flug et al 1984, Benso et al 1989, Malina et al 1994, Cameron and Nagdee 1996). The strength of this ‘genetic effect’, however, must be interpreted carefully as the mothers’ age at menarche was based on recall in most of these studies, and the accuracy of the estimation is therefore questionable. In addition, one must consider the effect of similarity in socio-economic status (and hence nutrition and fatness) that is likely to exist between mothers and daughters, and this in itself may contribute to similarity in menarcheal age.

The association between body weight and age at menarche has formed part of the basis for the explanation of the secular trend towards earlier menarche noted in the UK and other industrialized countries over the last century (Roberts et al 1971, Ostersehlt and Danker Hopf 1991). It has been generally accepted that this trend has reflected improvements in nutrition, health and environmental conditions. However, a recent plateau in this trend has been observed, and even reversal in some countries, which is at present unexplained (Dann and Roberts 1993, Tryggvadottir et al 1994, Veronesi and Gueresi 1994). It has been suggested that the recent decrease in menarcheal age is related to changes in social conditioning in developed countries. Promotion of very thin women as ‘ideal’ role models through media and fashion has contributed to an increase in dieting in adolescent girls. Increasing participation of women in endurance sports which have intense training regimens may also be a factor related to lower body weight in young girls.

These studies all indicate that pubertal development and body weight are intrinsically linked. However, the mechanism for this relationship has not been defined conclusively. Insulin has been suggested as a modulator of the tempo of pubertal development through the regulation of IGFBP-1 and SHBG (Smith et al 1988, Holly et al 1989, Nobels and Dewailly 1992). States of overnutrition and obesity are associated with increased serum concentrations of insulin (Parra et al 1971, Rosenbaum et al 1997). Therefore, if excessive nutritional intake persists during childhood, it is possible that hyperinsulinaemia may lead to lower levels of IGFBP-1 and reduced SHBG concentrations, thus enhancing IGF-1 and sex steroid bioavailability. The converse would be true in states of malnutrition, where low levels of insulin would allow for the development of increased IGFBP-1 and SHBG levels.

However, it is still unclear whether hyperinsulinaemia in childhood is a result of obesity or if it is the cause of obesity. The roles of genetic factors, which may determine insulin production and obesity risk in childhood, are also yet to be clearly explained. Recently, there has been much interest in the actions of the newly identified hormone leptin which is produced by adipose tissue (Sorensen et al 1996). Serum concentrations of leptin, a 167 amino acid product of white fat, have been shown to be related to body fat mass, and it is believed that leptin exerts its action on the hypothalamus to control calorie intake, decrease thermogenesis, increase levels of serum insulin and increase pulsatility of GnRH (Considine et al 1996, Sorensen et al 1996). With these actions, leptin may potentially have a role in the hormonal control of pubertal development, and some studies have shown that leptin levels do increase before the onset of puberty (Clayton et al 1997, Mantzoros et al 1997). It has been postulated that changes in circulating leptin levels may act as an initiator for the onset of puberty, and that this may explain the relationships between body fat and maturation observed by Frisch and Revelle (1970). This hypothesis is supported by the recent work of Clement et al (1998), who identified a homozygous mutation of the leptin receptor gene which results in early-onset morbid obesity and the absence of pubertal development in association with reduced GH secretion. These findings suggest that increased leptin levels associated with gains in fat mass may signal the hypothalamus to act as an important regulator of sexual maturation. It is possible that future research may clarify the role of leptin and leptin receptors in pubertal development, and may explain the variation in the timing of onset of puberty between individuals.

Ovarian and uterine development

Development of primordial follicles and secretion of oestrogens may be regarded as the final common path in the hormonal activity of puberty, and there is a close correlation between oestrogen levels and sexual maturation. The uterus grows in concordance with somatic growth, with differential increased growth of the corpus starting from approximately 7 years of age. However, the main differential increase of uterine size compared with somatic growth is only obvious after oestradiol secretion is measurably increased, and tends to occur between breast stages 3 and 4. Awareness of this comparatively late relative increase in uterine size has clinical relevance in the differentiation of arrested puberty and Müllerian agenesis, and also in the diagnosis of causes of precocious puberty. Blood oestrogen levels rise before and during puberty, and continue to do so for approximately 3 years after menarche before the normal adult follicular levels of oestrogen are seen. This gradual maturation is a reflection of the finding that many of the early cycles are anovulatory, and of the observation that the early postmenarcheal years are relatively infertile.

Ultrasound is the most suitable imaging technique for examination of the internal genitalia of girls as it is free from the risks of radiation and involves a quick, quiet and non-invasive procedure. Whilst higher resolution images can be obtained of the ovaries and uterus using transvaginal ultrasonography, only the transabdominal approach can be used in young girls and it may not always be possible to visualize both ovaries; furthermore, a full bladder is required. Nonetheless, transabdominal ultrasonography is an invaluable tool for the delineation of normal changes before and through puberty, and also for the evaluation of paediatric disorders, such as pelvic masses and abnormal pubertal development. Ultrasonography can also be used in postmenarcheal girls to detect abnormal ovarian morphology and hence increase our understanding of common conditions such as polycystic ovary syndrome.

There are relatively few normal data on the maturation of the internal genitalia in girls, and a paper by Holm et al (1995) provides cross-sectional data of a large cohort of 166 school girls and medical students. It was demonstrated that uterine and ovarian volumes increase in size prepubertally, from as early as 6 years of age. Griffin et al (1995) demonstrated similar changes from the age of 4 years and, in their study of 153 girls, included subjects as young as 3 days. It was found that uterine shape changes constantly throughout childhood from a pear shape to a cylindrical shape and, finally, to the adult heart shape.

As girls go through puberty, the ovaries have been described as characteristically becoming multicystic due to low levels of FSH stimulating only partial folliculogenesis (Stanhope et al 1985). The multicystic appearance is also seen during resumption of ovarian activity after periods of quiescence; for example, in women who are recovering from weight-related amenorrhoea or those with hypogonadotrophic hypogonadism who are treated with pulsatile GnRH. The multicystic ovary differs from the polycystic ovary in that the cysts are larger (6–10 mm) and the stroma is of normal echogenicity. The morphological appearance of the polycystic ovary, on the other hand, requires the presence of at least 10 cysts (2–8 mm) per ovary in the presence of an echodense stroma (see Chapter 18).

Menarche

The first period occurs because there has been sufficient endometrial stimulation to result in a withdrawal bleed when there is a temporary fall in the oestrogen level. It can be associated with an ovulatory/corpus luteum sequence but this is not usual. The first menstruation simply indicates that a particular threshold has been reached in an already oscillating system, but is an obvious outward sign and of significance; menarche denotes an intact hypothalamic–pituitary–ovarian axis, functioning ovaries, the presence of a uterus and patency of the genital tract.

Menarche generally occurs within 2 years of the earliest sign of breast development and within 1 year of peak growth velocity and close to breast stage 4, usually between the ages of 10 and 16 years.

True precocious puberty

The appearance of pubertal physical features follows the normal sequence (‘consonance’), beginning with breast development. The diagnosis is made by the finding of elevated basal gonadotrophin levels and, after stimulation with i.v. GnRH, the serum LH concentration is higher than FSH. It is important to consider intracranial pathology and arrange imaging if indicated. Pelvic ultrasound will reveal the presence of multicystic ovaries and a uterus that is developing adult proportions. Bone age will be advanced.

Premature thelarche

Premature breast development in the absence of other signs of puberty may present at any age from infancy. Breast size may fluctuate and is often asymmetrical. Bone maturation, growth rate and final height are unaffected. The cause is unknown. The diagnosis is made by the finding of elevated FSH levels (but not LH), both basal and following GnRH stimulation. Ovarian ultrasound often reveals a single large, functional ovarian cyst. Serum oestradiol concentrations are usually low and bone age is unaffected. It is important to monitor carefully in order to exclude the onset of true precocious puberty.

Autoimmune hypothyroidism may also result in isolated breast development, although this is rarely seen before 5 years of age.

Thelarche variants

There appears to be a whole spectrum of presentations between premature thelarche and true precocious puberty. Thus, some girls with early breast development also demonstrate increased height velocity and bone maturation, and ovarian ultrasound reveals a multicystic appearance (as distinct from polycystic, see Chapter 18).

Premature adrenarche

The normal onset of adrenal androgen secretion (‘adrenarche’) occurs 1–2 years prior to the onset of puberty. ‘Premature’ or ‘exaggerated’ adrenarche results in mild virilization (e.g. pubic hair and acne, but not clitoromegaly). The cause is unknown. The diagnosis is made by the finding of low serum gonadotrophin levels and mildly elevated adrenal androgen levels (dehydroepiandrosterone sulphate, androstenedione). It is important to exclude late-onset congenital adrenal hyperplasia (CAH) and androgen-secreting tumours.

Congenital adrenal hyperplasia

CAH due to deficiency of the enzyme 21-hydroxylase leads to cortisol deficiency, oversecretion of adrenocorticotrophic hormone (ACTH) due to loss of feedback inhibition, and excessive production of adrenal androgens (see Chapter 11). Inheritance is autosomal recessive. Classic CAH usually presents in the neonate with ambiguous genitalia and a salt-losing crisis (see Chapter 13), whilst non-classic or late-onset CAH presents in adolescence with moderate to severe virilization (pubic hair, hirsutism, acne and clitoromegaly) and rapid growth.

The diagnosis is made by the finding of raised levels of cortisol precursors, particularly 17-OH progesterone, both at baseline and post i.v. ACTH stimulation, in both plasma and urine. Gonadotrophin levels are suppressed. Bilateral adrenal hyperplasia may be seen on abdominal ultrasound. Management of CAH is by hydrocortisone replacement therapy, which suppresses ACTH and adrenal androgen secretion (the classic presentation may also require fludrocortisone to replace aldosterone secretion).

Androgenization of the female external genitalia may lead not only to clitoromegaly but also fusion of the labioscrotal folds. There may, in addition, be a urethral fistula which may require careful repair at the time of an introitoplasty. Clitoral reduction should be undertaken with care to preserve the neurovascular bundle and sensation. Surgery may be undertaken during the neonatal period, and may be required again during adolescence. As with all surgery for intersex disorders, the precise timing is open to debate, as is the degree to which the patient, rather than her parents and doctors, is involved in the decision-making process.

Peripheral tumours

McCune–Albright syndrome

This sporadic condition results in spontaneous activation of gonadotrophin receptors and excessive sex steroid secretion independent of normal ligand binding. It is due to a somatic activating mutation of the G-protein α-subunit which also affects bones (polyostotic fibrous dysplasia), skin (café au lait spots) and potentially multiple other endocrinopathies (hyperthyroidism or hyperparathyroidism). All cells descended from the mutated embryonic cell line are affected, while cells descended from non-mutated cells develop into normal tissues. Thus, the phenotype is highly variable in physical distribution and severity. The diagnosis is made by clinical assessment, based on the presence of skin, bone and other lesions. Biopsy of affected skin may allow identification of the genetic mutation. Gonadotrophin levels are suppressed.

Management of precocious puberty

It is important to exclude severe diseases (e.g. CAH, cranial or peripheral tumours) which will require specific therapy. Following reduction in peripheral sex steroid levels, due to CAH or sex-steroid-secreting tumours, central precocious puberty may occur due to hypothalamic maturation (especially if the girl’s bone age is already >11 years). Premature thelarche and thelarche variant need no treatment as there are no long-term consequences and, furthermore, treatment appears to be without effect.

Constitutional delay of growth and puberty

Rates of skeletal and sexual maturation are closely linked, but vary widely between individuals and are influenced by family history and rate of early childhood weight gain. Although constitutional delay presents more commonly in males, this may merely reflect their higher level of concern. These girls are otherwise healthy. The diagnosis is made by exclusion, but often can only be confirmed retrospectively following spontaneous initiation of the hypothalamic–pituitary axis. It can be very difficult to distinguish hypogonadotrophic hypogonadism from constitutional delay in puberty, and therefore it is better to provide treatment and revisit the diagnosis at a later date. Appropriate investigations, after physical examination and measurement of weight and height, include assessment of serum concentrations of gonadotrophins, prolactin and thyroid function, and assessment of bone age (radial X-ray). Pelvic ultrasonography may be helpful, as is a karyotype if features of Turner’s syndrome are suspected.

Turner’s syndrome

Characteristic features of Turner’s syndrome may not be obvious, particularly if due to chromosomal mosaicism, and karyotype should be investigated in all girls presenting with pubertal delay. Up to 25% of girls with Turner’s syndrome enter puberty spontaneously; however, only 10% progress through puberty and only 1% develop ovulatory cycles. Thus, the chromosomal abnormality seems to result in premature ovarian exhaustion rather than a primary failure of ovarian development. Turner’s syndrome is the most common cause of gonadal dysgenesis. In its most severe form, the XO genotype is associated with the classic Turner’s features including short stature, webbing of the neck, cubitus valgus, widely spaced nipples, cardiac and renal abnormalities, and often autoimmune hypothyroidism. Spontaneous menstruation may occur (particularly when there is mosaicism), but premature ovarian failure (POF) usually ensues.

The clinical diagnosis is confirmed by the finding of a 45XO karyotype (at least 30 cells should be examined due to the possibility of mosaicism). Cytogenetic analysis should also be performed looking for the presence of Y fragments, which indicate an increased risk of gonadoblastoma, and thus the ‘streak’ gonads should be removed (usually laparoscopically). Serum gonadotrophin concentrations are elevated compared with adolescents of the same age, and may approach the menopausal range.

Management includes low-dose oestrogen therapy to promote breast development without further disturbing linear growth (Figure 14.6). Treatment with GH has also benefited some individuals. Cyclical oestrogen plus progestogen may be used as maintenance therapy. A regular withdrawal bleed is essential in order to prevent endometrial hyperplasia. Spontaneous conception has been reported in patients with Turner’s syndrome, but is rare. However, the possibility of assisted conception and oocyte donation should be discussed at an early age.

Figure 14.6 Breast development in Turner’s syndrome following oestrogen administration. There is good areolar development but little breast tissue after several years of hormone replacement.

Other causes of premature ovarian failure

POF, by definition, is the cessation of periods accompanied by raised gonadotrophin concentration prior to the age of 40 years. It may occur at any age. The exact incidence of this condition is unknown as many cases go unrecognized, but estimates vary between 1% and 5% of the female population (Coulam et al 1986). In approximately two-thirds of cases, the cause of ovarian failure cannot be identified (Conway et al 1996). It is unknown whether these cases are truly ‘idiopathic’ or due to as yet undiscovered genetic, immunological or environmental factors. A series of 323 women with POF attending an endocrinology clinic in London identified 23% with Turner’s syndrome, 6% after chemotherapy, 4% with familial POF and 2% each who had pelvic surgery, pelvic irradiation, galactosaemia and 46XY gonadal dysgenesis (Conway et al 1996). Viral and bacterial infection may also lead to ovarian failure; thus, infections such as mumps, cytomegalovirus or human immunodeficiency virus in adult life can adversely affect long-term ovarian function, as can severe pelvic inflammatory disease.

Ovarian failure occurring before puberty is usually due to a chromosomal abnormality or a childhood malignancy that required chemotherapy or radiotherapy, from which, parenthetically, there are increasing numbers of survivors into adulthood with POF. The likelihood of developing ovarian failure after therapy for cancer is difficult to predict, but the age of the patient is a significant factor; the younger the patient, the greater the follicle pool and the better her chances of retaining ovarian function.

Adolescents who lose ovarian function soon after menarche are often found to have a Turner’s mosaic (46XX/45X) or an X-chromosome trisomy (47XXX). There are many genes on the X chromosome that are essential for normal ovarian function. It would appear that two active X chromosomes are required during fetal life in order to lay down a normal follicle store. In fetuses with Turner’s syndrome, normal numbers of oocytes appear on the genital ridge but accelerated atresia takes place during late fetal life. Thus, streak gonads occur and it is only the mosaic form of Turner’s syndrome that permits any possibility of ovarian function. X mosaicisms are the most common chromosomal abnormality in reported series of POF, ranging from 5% to 40% (Anasti 1998). Other X chromosome anomalies may result in ovarian failure; for example, balanced translocations in the long arm of chromosome X between Xq13 and q26, which is a critical region for ovarian function.

There are a number of syndromes that are associated with POF, such as familial blepharophimosis, in which the abnormality is on chromosome 3. Galactosaemia is another rare example, in which a metabolic defect has a direct inhibitory effect on ovarian function, probably due to a build-up of galactose within the ovary that decreases the initial number of oogonia.

Polyglandular autoimmune syndromes

Antiovarian antibodies are occasionally detected in both type 1 (hypoparathyroidism, Addison’s disease, mucocutaneous candidiasis) and type 2 (Addison’s disease, hypothyroidism, type 1 diabetes) polyglandular autoimmune syndromes. Autoimmune ovarian failure may also occur in the absence of positive antibodies due to poor sensitivity of current assays.

Congenital hypogonadotrophic hypogonadism

Congenital hypogonadotrophic deficiency associated with complete or partial anosmia ± other midline defects and mental retardation (Kallman or DeMorsier syndrome) may be inherited in autosomal-dominant, -recessive or X-linked recessive patterns, suggesting that a number of mutated genes may be causative. Congenital hypogonadotrophism may also occur without anosmia in isolation or in pan-hypopituitarism. The diagnosis is made by a family history or related features of Kallman syndrome. Absent LH and FSH response to i.v. GnRH stimulation may be indistinguishable from constitutional delay of puberty, and retesting may be required after completing pubertal development with exogenous oestrogen.

Management of delayed puberty

Following exclusion of other diagnoses, many patients are happy to await spontaneous pubertal development. However, severe delay in pubertal onset may be a risk factor for decreased bone mineral density and osteoporosis. In subjects with hypergonadotrophic hypogonadism, puberty may be induced from any age; however, in Turner’s syndrome, delay in induction to around 14 years of age possibly permits maximal response to GH therapy (see Box 14.3).

Müllerian duct abnormalities

In the absence of a Y chromosome, testis and testosterone, the Wolffian duct regresses after the sixth week of embryonic life. The Müllerian ducts then develop into the uterus and fallopian tubes, and fuse caudally with the urogenital sinus to form the vagina. Abnormalities in the process of fusion may be either medial or vertical, and result in primary amenorrhoea; complete or partial Müllerian agenesis may also occur. Renal developmental abnormalities are commonly seen in association with abnormalities of the genital tract, so assessment by intravenous urography is advisable before attempting corrective surgery.

Congenital absence of the vagina

Women with Mayer–Rokitansky–Kuster–Hauser syndrome (or Rokitansky syndrome) have a 46XX genotype and a normal female phenotype with spontaneous development of secondary sexual characteristics, as ovarian tissue is present and functions normally. The Müllerian ducts have failed to fuse and so there is vaginal agenesis. The incidence is about 1 : 5000 female births and may be associated with renal tract anomalies (15–40%) or anomalies of the skeletal system (10–20%). The external genitalia have a normal appearance but the vagina is short and blind ending, such that either surgery or gradual dilatation is necessary to achieve a capacity appropriate for normal sexual function. Hormone treatment is not required as ovarian oestrogen output is normal. Indeed, ovulation occurs and ovarian stimulation followed by oocyte retrieval can be performed in order to achieve a ‘biological’ pregnancy through the services of a surrogate mother.

The vaginal dimple can vary in length from just a slight depression between the labia to up to 5–6 cm. Vaginal dilators, made of plastic or glass, are used first to stretch the vaginal skin, and the patient is encouraged to apply pressure for 15 min twice daily with successive sizes of dilator. An adequately sized vagina is usually formed by 6 months but this may take longer, and long-term use of dilators may be required depending upon the frequency of sexual intercourse.

A number of surgical approaches have been employed to create a neovagina. The Vecchetti procedure uses the same principle of progressive dilatation, with the application of pressure from a plastic sphere in the vagina which is attached to two wires that have been passed from the top of the vagina through to the anterior wall of the abdomen, where they are attached to a traction device that is tightened daily. Plastic surgical techniques include:

The diagnosis of Rokitansky syndrome can usually be made without the need for a laparoscopy. Sometimes, however, an ultrasound scan will reveal the presence of a uterine remnant (anlagan) which is usually small and hardly ever of sufficient size to function normally. If there is active endometrial tissue within the uterine anlagan, the patient may experience cyclical pain and the anlagan should be excised (usually laparoscopically).

Müllerian/uterine anomalies

Uterine anomalies occur in 3–10% of the fertile female population and can be subdivided according to the nature of the abnormality. They been usefully classified by the American Society for Reproductive Medicine into six groups:

These anomalies are often discovered by chance during coincidental investigations for infertility. The diagnosis is made by a combination of ultrasound, magnetic resonance imaging and X-ray hysterosalpingography (the latter during the course of an infertility work-up). Women with uterine anomalies are usually asymptomatic, unless there is obstruction to menstrual flow, when cyclical pain may be experienced. Whilst infertility per se is rarely caused by uterine anomalies, they may be associated with endometriosis if there is retrograde menstruation secondary to obstruction. Furthermore, recurrent miscarriage may be experienced by some women with uterine malformations.

Surgery is reserved for those cases where there is obstruction; for example, the removal of a rudimentary uterine horn or excision of a vaginal septum. The excision of a uterine septum has been shown to improve pregnancy outcome and should be performed by an experienced hysteroscopist. On the other hand, metroplasty (Strassman procedure) of the horns of a bicornuate uterus is seldom performed nowadays as its benefit has been questioned.

Androgen insensitivity syndrome

Girls who are phenotypically normal but have absent pubic and axillary hair in the presence of normal breast development are likely to have complete androgen insensitivity syndrome (formerly known as ‘testicular feminization syndrome’, a term that is no longer favoured). In this condition, the karyotype is 46XY and, whilst testes are present, there is an insensitivity to secreted androgens because of abnormalities in the androgen receptor. The incidence is approximately 1 : 60,000 ‘male’ births and it is inherited as an X-linked trait (the androgen receptor is on the short arm of the X chromosome). Anti-Müllerian factors prevent the development of internal Müllerian structures, and the Wolffian structures also fail to develop because of the insensitivity to testosterone. The external genitalia appear female. In approximately 10% of cases, the defect is incomplete (partial androgen insensitivity syndrome); the external genitalia may be ambiguous at birth, with labioscrotal fusion, and virilization may sometimes occur before puberty.

After puberty, gonadal tissue should be removed to prevent malignant transformation (dysgerminoma), which occurs in approximately 5% of cases. Exogenous oestrogen should then be prescribed; cyclical treatment is not required because the uterus is absent. The syndrome may be diagnosed in infancy if a testis is found in either the labia or an inguinal hernia, in which case both testes should be removed at this time because of the potential risk of malignancy. Some cases, however, only present at puberty with primary amenorrhoea, and removal of abdominal/inguinal testes should then be performed.

Careful psychological assessment and counselling are obligatory to allow an understanding of the gonadal dysfunction and necessity for hormone treatment. It may be helpful to describe the gonads as internal sexual organs that have been incompletely formed and which are therefore prone to develop cancer if they are not removed. In general, a completely honest approach is favoured so that the individual is provided with full information about her condition, its origins and management. It is certainly the author’s experience that the vast majority of patients desire a full explanation of their condition, and respond better to treatment if they are included in the decision-making processes. Patients with these problems should be referred to centres where there are specialists experienced in their management, so that a comprehensive team approach can be provided.

There are several uncommon intersex disorders which result in primary amenorrhoea, and while their management must be individualized, it will often broadly follow the above outline. Examples are male pseudohermaphroditism, caused by 5α-reductase deficiency, and female pseudohermaphroditism, caused by CAH (see above). In contrast to the androgen insensitivity syndrome, in these conditions, there is deficient or absent breast development, yet normal or increased pubic and axillary hair. 5α-reductase deficiency is an autosomal-recessive condition, diagnosed by the presence of undervirilization (which may change at puberty) and an elevated testosterone:dihydrotestoster-one ratio.

Cloacal anomalies

Cloacal anomalies may take a variety of forms depending upon the relative contribution of gastrointestinal, genital and renal tracts. The cloaca should be divided anteriorly into the urogenital sinus, and posteriorly into the rectum. Major surgery is often required during the neonatal period to provide anterior abdominal wall integrity and continence of faeces and urine. Several operations may be required, and the uterus and genitalia, if present, may be adversely affected such that, at puberty, there is obstruction to menstrual flow and also an increased rate of ovarian cyst formation, presumably due to ovarian entrapment restricting normal follicular growth and ovulation.

Menorrhagia

In a young woman with intractable menorrhagia, an assessment of blood clotting may be beneficial. Disorders of haemostasis such as von Willebrand’s disease, deficiencies of factors V, VII, X and XI, and idiopathic thrombocytopenic purpura are thought to increase menstrual loss. Young girls with heavy periods in the years after the menarche are very unlikely to have any pelvic pathology. A very small number of young girls have persistent heavy irregular periods associated with anovular cycles, particularly those with polycystic ovary syndrome (see Chapter 18). In these cases, sustained unopposed oestrogen levels lead to endometrial hyperplasia which may ultimately progress to carcinoma.

Primary dysmenorrhoea

In general, primary dysmenorrhoea appears 6–12 months after the menarche when ovulatory cycles have become established. The early cycles after the menarche are usually anovular and tend to be painless. The pain usually consists of lower abdominal cramps and backache, and there may be associated gastrointestinal disturbances such as diarrhoea and vomiting. Symptoms occur predominantly during the first 2 days of menstruation. Primary dysmenorrhoea does not tend to be associated with excessive menstrual bleeding. Although excessive levels of prostaglandins, leukotrienes and vasopressin have been found in primary dysmenorrhoea, the primary stimulus for their production remains unknown. The clear involvement of prostaglandins in primary dysmenorrhoea has led to the use of prostaglandin synthetase inhibitors, such as mefenamic acid, naproxen, ibuprofen and aspirin, to treat the disorder. Ibuprofen is the preferred analgesic because of its favourable efficacy and safety profiles.