Textbook Of Gynecology. Dc Dutta’s

Chapter 5. Puberty Normal and Abnormal

PUBERTY

Definition

Puberty in girls is the period, which links childhood to adulthood. It is the period of gradual development of secondary sexual characters. There are profound biological, morphological, and psychological changes that lead to full sexual maturity and eventually fertility.

Morphological Changes

As described by Tanner and Marshall, five important physical changes are evident during puberty. These are breast, pubic and axillary hair growth, growth in height, and menstruation. Most of the changes occur gradually but only the menarche can be dated. Moreover, there is a lot of variations in the timing of the events. The most common order is beginning of the growth spurt → breast budding (thelarche) → pubic and axillary hair growth (adrenarche) → peak growth in height → menstruation (menarche). All these changes are usually completed between the age of 10 and 16 years.

Important controlling factors for onset of puberty are genetic, nutrition, body weight, psychologic state, social and cultural background, exposure to light and others. A girl, living in urban areas with good nutrition, adequate body weight and whose mother and sisters have early menarche, starts puberty early. Blind girls start menarche early.

ENDOCRINOLOGY IN PUBERTY

The levels of gonadal steroids and gonadotropins are low until the age of 6-8 years. This is mainly due to the negative feedback effect of estrogen to the hypothalamic pituitary system (Gonadostat). The gonadostat remains very sensitive (6-15 times) to the negative feedback effect, even though the level of estradiol is very low (10 pg/mL) during that time. As puberty approaches this negative feedback effect of estrogen is gradually lost (see p. 77). This results in some significant changes in the endocrine function of the girl.

 Hypothalamopituitary gonadal axis

The GnRH pulses from hypothalamus results in pulsatile gonadotropin secretion (first during the night then by the day time).

GnRH  FSH, LH  Estradiol

The tonic and episodic secretion of gonadotropins in prepubertal period is gradually changed to one of cyclic release in postpubertal period (details in p. 77, Fig. 7.6).

 Thyroid gland plays an active role in the hypothalamopituitary-gonadal axis.

 Adrenal glands (Adrenarche) increase their activity of sex steroid synthesis (androstenedione, DHA, DHAS) from about 7 years of age. Increased sebum formation, pubic and axillary hair and change in voice are primarily due to adrenal androgen production.

 GonadarcheIncreased amplitude and frequency of GnRH  ↑ secretion of FSH and LH  ovarian follicular development  ↑ estrogen. Gonadal estrogen is responsible for the development of uterus, vagina, vulva and also the breasts (see p. 50).

 Leptin, a peptide, secreted in the adipose tissue is also involved in pubertal changes and menarche (see p. 460).

Menarche

The onset of first menstruation in life is called menarche. It may occur anywhere between 10 and 16 years, the peak time being 13 years. There is endometrial proliferation due to ovarian estrogen but when the level drops temporarily, the endometrium sheds and bleeding is visible. It denotes an intact hypothalamo-pituitary-ovarian axis, functioning ovaries, presence of responsive endometrium to the endogenous ovarian steroids and the presence of a patent uterovaginal canal. The first period is usually anovular. The ovulation may be irregular for a variable period following menarche and may take about 2 years for regular ovulation to occur. The menses may be irregular to start with.

Growth

Growth in height in an adolescent girl is mainly due to hormones. The important hormones are growth hormone, estrogen and insulin like growth factor-1 (IGF-1). The bone or skeletal age is determined by X-ray of hand or knee.

Genital Organ Changes

Ovaries change their shape, the elongated shape becomes bulky and oval. The ovarian bulk is due to follicular enlargement at various stages of development and proliferation of stromal cells.

The uterine body and the cervix ratio at birth is about 1 : 2, the ratio becomes 1 : 1 when menarche occurs. Thereafter, the enlargement of the body occurs rapidly, so that the ratio soon becomes 2: 1 (Fig. 5.1).

TABLE 5.1 PANNERSTAGESOFPUBeRtALDEVELOPMENTINGRL

Stage

Breast Pubic hair

Stage I

Prepubertal state, elevation of papilla only

No pubic hair present

Stage II

Breast buds and papilla slightly elevated, and side of labia areola begins to enlarge. (Median age: 9.8 years)

Sparse, long hair on either majora. (Median age: 10.5 years)

Stage III

Further enlargement of entire breast tissue

Darker, coarser and curly hair over the mons pubis

Stage IV

Secondary mound of areola and papilla projecting above the breast tissue. (Median age:

12.1 years)

Adult type hair covering the mons only. (Median age: 12.0 years)

Stage V

Areola recessed to general contour of breast. (Median age : 14.6 years)

Adult hair with an inverse triangle distribution (female escutcheon) covering the medial thighs. (Median age: 13.7 years)

Fig. 5.1: Changes in the size of the uterus from birth to 75 years of age. Note the change in the relation of the cervix to the body

The vaginal changes are more pronounced. A few layers of thin epithelium in a child become stratified epithelium of many layers. The cells are rich in glycogen due to estrogen. Doderlein’s bacilli appear which convert glycogen into lactic acid; the vaginal pH becomes acidic, ranging between 4 and 5.

The vulva is more reactive to steroid hormones.

The mons pubis and the labia minora increase in size.

Breast changes are pronounced. Under the influence of estrogen, there is marked proliferation of duct systems and deposition of fat. The breast becomes prominent and round. Under the influence of progesterone, the development of acini increases considerably.

Tanner staging: According to Tanner, breast and pubic hair development at puberty are divided into five stages (Table 5.1).

COMMON DISORDERS OF PUBERTY

* Precocious puberty

 Delayed puberty

* Menstrual abnormalities (amenorrhea, menorrhagia, dysmenorrhea)

 Others (infection, neoplasm, hirsutism, etc.) see Ch. 32.

PRECOCIOUS PUBERTY

DEFINITION

The term precocious puberty is reserved for girls who exhibit any secondary sex characteristics before the age of 8 or menstruate before the age of 10.

Precocious puberty may be isosexual where the features are due to excess production of estrogen. It may be heterosexual where features are due to excess production of androgen (from ovarian and adrenal neoplasm).

TYPES OR CAUSES

The causes are tabulated in the Table 5.2.

ETIOPATHOLOGY

Constitutional

It is due to premature activation of hypothalamo- pituitary ovarian axis. There is secretion of gonadotropins and gonadal steroids due to premature release of GnRH. Bone maturation is accelerated, leading to premature closure of the epiphysis and curtailed stature. If menstruation occurs, they may be ovulatory. The changes in puberty progress in an orderly sequence.

Intracranial lesions

Meningitis, encephalitis, craniopharyngioma, neurofibroma or any tumor—hypothalamic or pineal gland.

McCune-Albright syndrome is characterized by sexual precocity, multiple cystic bone lesions (polyostotic fibrous dysplasia), endocrinopathies and cafe-au-lait spots on the skin. Sexual precocity is due to early and excessive estrogen production from the ovaries. FSH, LH levels are low. There may be associated hyperthyroidism, hyperparathyroidism, and acromegaly.

Premature thelarche

It is the isolated development of breast tissue before the age of 8 and commonly between 2 and 4 years of age. Either one or both the breasts may be enlarged (Fig. 5.2). There is no other feature of precocious puberty. It generally requires no treatment.

Premature pubarche

Premature pubarche is isolated development of axillary and or pubic hair prior to the age of 8 without other signs of precocious puberty. The premature hair growth may be due to unusual sensitivity of endorgans to the usual low level of hormones in the blood during childhood. Rarely, there may be signs of excess androgen production due to adrenal hyperplasia or tumor or androgenic ovarian tumor (Leydig cell tumor, androblastoma, etc.).

Fig. 5.2: Precocious puberty in a girl aged 2 years and 3 months

Premature menarche

Premature menarche is an isolated event of cyclic vaginal bleeding without any other signs of secondary sexual development. The cause remains unclear but may be related to unusual endocrine sensitivity of the endometrium to the low level of estrogens.

Chorionic epithelioma, hepatoblastoma are the ectopic sources of human chorionic gonadotropin and may cause sexual precocity.

DIAGNOSIS

True precocious

Constitutional type is the commonest one but the rare one is to be kept in mind. The diagnosis is made by:

 History of early menarche of mother and sisters

 The pubertal changes occur in orderly sequence

 Tanner stages

 No cause could be detected.

The basic investigations, to confirm or to exclude some pathologic lesions, include:

 X-ray hand and wrist (non-dominant) for bone age. Acceleration of growth is one of the earliest clinical features of precocious puberty

 Pelvic sonography to exclude ovarian pathology

 Skull X-ray, CT scan, or MRI brain—to exclude intracranial lesion

 Serum hCG, FSH, LH

 Thyroid profile (TSH, T4)

 Serum estradiol, testosterone, 17 OH progesterone, dehydroepiandrosterone (DHEA).

 Electroencephalogram.

Premature thelarche

 Somatic growth pattern is not accelerated

 Bone age is not advanced

 Nipple development is absent

 Vaginal smear shows negative estrogen effect.

Premature pubarche

It may be due to adrenal or ovarian mischief. As such, the investigations are directed accordingly.

 An ovarian enlargement may not be palpable clinically. Examination under anesthesia or sonography is helpful

 IVP or CT scan is required to detect adrenal tumor.

 Estimations of serum 17 a-hydroxyprogesterone, DHEA-S and serum testosterone are to be done in suspected cases of adrenal mischief—hyperplasia or tumor.

If nothing abnormal is detected, then the diagnosis of idiopathic pubarche is made.

Premature menarche

The other causes of vaginal bleeding, such as foreign body or injury has to be excluded. If the bleeding is cyclic, the diagnosis is confirmed.

Remarks

Investigations must be carried out to rule out any pathology in the CNS, ovary, and adrenal. It should be borne in mind that even in cases when no cause can be detected in any of the types mentioned, the periodic evaluation at 6 monthly intervals is to be made to detect any life-threatening pathology at the earliest.

TREATMENT

The treatment depends upon the cause. The exogenous estrogen therapy or its inadvertent intake should be stopped forthwith. Cortisone therapy for adrenal hyperplasia and surgery to remove the adrenal or ovarian tumor eliminate the excess source of either androgen or estrogen. The intracranial tumor requires neurosurgery or radiotherapy. Primary hypothyroidism needs thyroid replacement therapy.

CONSTITUTIONAL OR IDIOPATHIC TYPE

The goals are:

 To reduce gonadotropin secretions.

 To suppress gonadal steroidogenesis or counteract the peripheral action of sex steroids.

 To decrease the growth rate to normal and slowing the skeletal maturation.

 To protect the girl from sex abuse.

The drugs used are:

► GnRH agonist therapy arrests the pubertal precocity and growth velocity significantly. The agonists suppress the premature activation of hypothalamopituitary axis due to down regulation and thereby diminished estrogen secretion. GnRH agonist therapy is the drug of choice in cases with GnRH dependent precocious puberty. Therapy should be started as soon as the diagnosis is established. GnRH agonist therapy suppresses FSH, LH secretion, reverses the ovarian cycle, establishes amenorrhea, causes regression of breast, pubic hair changes, and other secondary sexual characteristics. This drug should be continued till the median age of puberty (see p. 49).

Dose: Buserelin nasal spray 100 µg daily. It can slow down the process of skeletal maturation. Depot forms (goserelin or leuprolide) once a month can be used (see p. 525). Dose is adjusted to maintain the serum estradiol below 10 pg/mL.

 Medroxyprogesterone acetate—30 mg daily orally or 100-200 mg. IM weekly to suppress gonadal steroids. It can suppress menstruation and breast development but cannot change the skeletal growth rate.

 Cyproterone acetate—It acts as a potent progestogen, having agonist effects on progesterone receptors.

Dose—70-100 mg/m2/day orally for 10 days starting from 5 th day of cycle.

 Danazol—It produces amenorrhea and arrest breast development. But there is no effect on growth rate or skeletal maturation.

Duration of therapy

The drugs should be used up to the age of 11 years. However, individualization is to be done.

PROGNOSIS

Prognosis varies considerably depending on the etiology. Overall prognosis is good with primary hypothyroidism, adrenal or ovarian tumors following treatment. For the CNS group, prognosis depends on neurological involvement and treatment outcome. Apart from the short stature due to accelerated bone maturation, the idiopathic group have got a normal menstrual pattern in future. The fertility rate is also expected to be normal.

DELAYED PUBERTY

Puberty is said to be delayed when the breast tissue and/or pubic hair have not appeared by 13-14 years or menarche appears as late as 16 years. The normal upper age limit of menarche is 15 years.

Treatment

Treatment is directed according to the etiology. Assurance, improvement of general health and treatment of any illness may be of help in nonendocrinal causes. Cases with hypogonadism may be treated with cyclic estrogen. Unopposed estrogen 0.3 mg (conjugated estrogen) daily is given for first 6 months. Then combined estrogen and progestin, sequential regimen is started (see Ch. 6). Cases of hypergonadotropic hypogonadism should have chromosomal study to exclude intersexuality (see p. 439).

PUBERTY MENORRHAGIA

Menstrual abnormality in adolescents are common.

The periods may be heavy, irregular or scanty initially.

Eventually the majority of these teenaged girls establish a normal cycle and are fertile.

The important causes of menorrhagia are:

iDysfunctional uterine bleeding (95%). Anovulatory cycles → unopposed estrogen → endometrial hyperplasia → prolonged and heavy periods (see p. 189).

ii. Endocrine dysfunction:

 Polycystic ovary syndrome (PCOS, see p. 459).

 Hypo- or hyperthyroidism.

iii. Hematological:

 Idiopathic thrombocytopenic purpura (see p. 185).

 Von-Willebrand’s disease (see p. 185).

 Leukaemia.

iv. Pelvic tumors:

 Fibroid uterus (see p. 272).

 Sarcoma botryroides (see p. 369).

 Estrogen producing ovarian tumor (see p. 384, 385).

vPregnancy complications (abortion).

Diagnosis is made by careful history taking and thorough clinical examination.

Evaluation is especially indicated if the menstrual interval is < 22 days or > 44 days, lasts longer than one week or the bleeding is too heavy that anemia develops.

Investigations are planned according to the clinical diagnosis. Investigations include, routine hematological examination, including bleeding time, clotting time, platelet count. Thyroid profile (TSH, T3, T4), clotting profile, and imaging study of the pelvis by ultrasonography may be needed. EUA and uterine curettage are rarely needed to exclude any pelvic pathology (pregnancy complications). The curetted material is sent for histopathological study.

Management: The girl needs adequate explanation, reassurance and psychological support. Rest and correction of anemia are helpful in majority of the cases.

Therapy with hematinics or even blood transfusion may be needed. In refractory cases, progestogens, such as medroxyprogesterone acetate or norethisterone 5 mg thrice daily is given till bleeding stops. Usually, the bleeding is controlled within 3-7 days. Medication is continued for 21 days. The condition usually becomes normal following 2-3 courses and then normal cycles resume. In emergency, conjugated equine estrogen 20-40 mg IV is given every 6-8 hours. Once the bleeding is controlled, combined oral pills are started (Flowchart 5.1).

Regular menstrual cycle will be established once the hypothalamo-pituitary-ovarian axis is matured.

KEY POINTS

> Puberty in girls is the period that binds childhood to adulthood.

The most common order of changes is beginning of growth spurt → Enlargement of the breast buds → Appearance of pubic hair → Axillary hair → Peak growth in height → Menstruation (menarche).

Uterine body and cervix ratio becomes 1 : 1 at menarche from 1 : 2 at birth. The ratio is 2 : 1 in adult.

> The term precocious puberty is reserved to those who exhibit any secondary sex characteristic before the age of 8 or menstruate before the age of 10. The common cause being constitutional.

The exact etiology of GnRH dependent (true) precocious puberty is not known. Central nervous system disease may be present in nearly 30% of cases. GnRH independent (pseudo) precocious puberty is mostly related to an ovarian or adrenal pathology.

> Life-threatening neoplasms (ovary, adrenal or CNS system) must be ruled out when a girl with precocious puberty is seen.

> The basic investigations include X-ray hand and wrist for bone age, pelvic sonography, skull X-ray, CT or MRI brain and electroencephalogram. Serum levels of FSH, LH, hCG, thyroid profile, 17 OH progesterone and testosterone are measured.

> The primary aim of management for a girl with precocious puberty is to (i) reduce the secretion of gonadotropins. (ii) block the peripheral action of sex steroids and (iii) slow down the growth rate, including skeletal maturation.

> GnRH agonist is the drug of choice. It suppresses FSH, LH secretion, reverses ovarian cycle, establishes amenorrhea, causes regression of breast, pubic hair changes and other secondary sexual characteristics (see p. 53).

The other drugs used for constitutional type to suppress the premature activation of hypothalamo-pituitary- gonadal axis are—medroxyprogesterone acetate, cyproterone acetate, and danazol.

> Delayed puberty is said to occur when the breast tissues and/or pubic hair have not appeared by 13-14 years or menarche as late as 17 years.

> Ovarian failure and chromosomal anomalies are the common causes of delayed puberty. Estimation of serum gonadotropins is important to differentiate hypogonadotropic from hypergonadotropic causes (Table 5.3).

> Initial periods may be excessive due to anovulation.

> Menstruation just after puberty and just before menopause are mostly anovulatory and often irregular in frequency.

> The important cases of puberty menorrhagia are: DUB, PCOS, thyroid disorders, hematological, pelvic tumors or pregnancy complications (see p. 54).

> Pubertal menorrhagia should be treated with rest, assurance, hematinics and blood transfusions. Hypothyroidism and thrombocytopenic purpura are to be excluded. Pelvic ultrasonography is needed to exclude any organic lesion. In refractory cases, progestins or conjugated estrogen are effective failing which, EUA and uterine curettage are to be done. The materials should be histologically examined.



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