Reproductive Growth and Development in the Female Adolescent
Melissa Slivka, Anna-Barbara Moscicki, and Mary-Ann Shafer
REPRODUCTIVE HEALTH
The normal reproductive physiological development in the adolescent permits the identification of pathologic conditions that deviate from the predictable sequence of hormonal, anatomic, and histologic changes of puberty. A comprehensive overview of the hypothalamic-pituitary-gonadal axis with the associated hormonal changes of puberty is presented in Chapter 540.
REPRODUCTIVE GROWTH AND DEVELOPMENT
BREAST
Major breast changes occur during 2 stages of reproductive development: puberty and pregnancy. The onset of breast development, or thelarche, heralds both anatomic and histo-logic changes in the breast. Estrogen is the most influential hormone affecting breast development during puberty. It binds to breast tissue, resulting in stimulation of growth of the glandular ductal system, whereas progesterone is linked to alveolar growth. Other hormones, including insulin, growth hormone, thyroxine, prolactin, and cortisol, and their interactions with estrogen, also play important roles in pubertal breast development.
There are 4 stages of breast development during the life cycle: prepuberty (atrophic ducts), puberty (lobuloalveolar and ductal growth), lactation (milk secretion), and senescence (regression to atrophic ducts). 
Abnormalities in development and breast masses are described in Chapter 74.
VAGINA
The vaginal epithelium is sensitive to hormonal influence. Sequential changes occur throughout the life cycle, including during birth, childhood, puberty, menstrual cycles, pregnancy, and menopause.
At birth, the vagina is 4 cm long, lengthens approximately 1 cm during early childhood and 8 cm during late childhood, and reaches mature length of 10 to 12 cm by menarche. During early puberty, increased estrogen levels affect the vaginal epithelia. Such pubertal changes can be noted on examination by identification of the more mature dull pink color of the vaginal mucosa, increased vaginal secretions, and increased vaginal wall flexibility compared with the prepubertal findings of the red translucent mucosa, sparse secretions, and a relatively rigid vaginal wall. The distal third of the vagina is one of the first sites to be affected by estrogen during puberty. The vaginal epithelium is made of 4 cell layers: basal, parabasal, intermediate, and superficial. The histology of the infant shows vaginal epithelium with a predominance of basal cells. In early childhood, the epithelium is 2 to 8 layers thick and consists of a definitive basal layer and parabasal intermediate cells. With the small increases of estrogen in late childhood, the intermediate cell layer proliferates, and the superficial cells undergo maturation. In the middle of puberty, the rise in estrogens results in the cornification (transformation of cell type) of the epithelium and development of a tissue layer 65 to 85 cells thick, which consists of predominantly mature squamous superficial cells. Up to 12 months before menarche, an increase in vaginal secretions may be noted, resulting from desquamated superficial and intermediate cells and mucoid secretions from maturing cervical and vestibular glands.1 These secretions are often reported by patients as a discharge with concerns about possible infection. The patient needs to be reassured about this normal physiologic process.
After birth, the neonatal vagina is temporarily colonized with lactobacilli that produce lactic acid, resulting in an acidic milieu. Within several weeks after birth, the vaginal flora changes and becomes predominantly colonized with enterococci and diphtheroids, and the pH becomes alkaline. This environment persists through childhood until puberty, when lactobacilli reappear in greater concentrations and again produce an acidic vaginal milieu. With the maturation of the vagina after menarche, cyclic changes in the vaginal histology occur with the menstrual cycle. Vaginal cytology can be helpful in evaluating the estrogen effect. The estrogen-induced vaginal changes provide a primary barrier to local trauma and infection.
UTERINE CERVIX
The growth and maturation of the cervix results primarily from the effects of estrogen stimulation.
In infancy and early childhood, the cervix appears as a 2-dimensional structure. The cervical os presents as a narrow slit in the posterior vaginal wall. With puberty, the cervix enlarges to a 3-dimensional knoblike structure that protrudes from the posterior vaginal wall. The nulliparous os is usually small, round in shape, and readily seen. During embryonic development, the cervix and vagina are initially lined with müllerian-type columnar cells, which are replaced by squamous epithelium from urogenital cells. This replacement is usually incomplete, and an area of columnar cells remains on the ectocervix (termed ectopy) with the border between the 2 different epithelia called the original squamocolumnar junction. At puberty, the acidic environment of the vagina and other hormonal influences trigger developmental changes leading to further replacement of the columnar epithelia with squamous epithelia. This process of change is called squamous metaplasia, and the area of change is referred to as the transformation zone.
Adolescents, in general, have greater areas of ectopy and active transformation zones than adult women.1,3 The areas of immaturity appear to be particularly vulnerable to sexually transmitted infections, including human papillomavirus (HPV), Chlamydia trachomatis, and Neisseria gonorrhoeae.4 It has been shown that most cervical neoplasias arise within the transformation zone.
Adolescents with large areas of active metaplasia may be at increased risk for the development of neoplasia when exposed to HPV and other oncogenic stimuli.5
Changes in the cervical mucus itself parallel those in epithelial cells during puberty. Premenarchial mucus is characteristically low in volume, viscous, sticky, and alkaline. Just before menarche, the cervical mucus may become copious, and as the estrogen level increases further, the mucus becomes elastic, translucent, acidic, and capable of producing a fern pattern on a glass slide. Such characteristics can be used to measure estrogen stimulation. 
UTERUS
Estrogen is the main stimulus for the remarkable growth of the uterus in both volume and weight that occurs during puberty, with the uterus increasing over 30-fold in volume.
At infancy, the uterus measures approximately 2.5 cm long and 1 cm wide and remains in this latent stage until about age 7 years.1 At this time, uterine growth resumes at an accelerated rate that peaks between ages 10 and 13 years. During childhood, the ratio of the body of the uterus to the cervix is approximately 1:1. At Tanner and Marshall SMR 2, growth of both the cervix and uterus accelerate. The ratio of uterine-to-cervix growth is extremely variable during puberty with a mean ratio of 1:2 post-menarchal.8 Histologically, the endometrium changes little until puberty. The rise of estrogen at the beginning of puberty stimulates endome-trial proliferation. Adequate rhythmic stimuli from the hypothalamic-pituitary-gonadal axis results in physiological rises and falls in estrogen. A sudden fall of estrogen in an estrogen-primed uterus will result in withdrawal bleeding, and menarche may occur even without ovulation. Anovulatory “breakthrough” bleeding associated with a proliferative endometrium is common within the first 2 to 4 years after menarche. The mean age of menarche in the United States is currently 12.6 years for white adolescents and slightly younger, 12.1 years, for black adolescents, with a normal range from 8 to 16 years.9
The endometrial structure undergoes dramatic hormonally influenced changes that result in either pregnancy or menstruation during each hypothalamic-pituitary-ovarian–mediated menstrual cycle (Fig. 64-1). These endome-trial changes include 5 phases: proliferation, secretory phase, implantation preparation, endometrial breakdown, and menstruation. The proliferation phase is primarily influenced by estrogen, runs parallel to ovarian follicle growth, results in the endometrial lining increasing from about 0.5 mm to 3.5 to 5.0 mm in height, and causes endometrial glands to become tortuous and dilated. The secretory phase is characterized by further maturation of the endometrial tissues under the influence of both estrogen and progesterone, which includes progressive tortuosity of the glands and coiling of the spiral arteries with no increase in endometrial height.
During the implantation preparation phase (days 8–14), the endometrium develops into 3 distinct layers: the basal layer, the stratum spongiosum, and a superficial layer. The corpus luteum (the residual ovarian follicle following release of the ovum) reaches its maximal progesterone-producing activity during this time (day 22). When implantation does not take place, the corpus luteum deteriorates, resulting in rapidly decreasing levels of estrogen and progesterone, which leads to the breakdown of the endometrium and menses.
OVARY
Ovarian growth is stimulated in large part by follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The ovaries themselves produce hormones, including estrogen and progesterone, for reproductive growth.
The ovary weighs 1 g at birth and 6 g by menarche. At birth, the development of the oocytes and primordial follicles is primarily complete. Maturing follicles become progressively larger before menarche and account for the rise in estrogen levels (Fig. 64-1). The follicles then begin to mature to the point required to produce adequate estrogen to promote menarche. At the critical level of estrogen necessary to produce an LH surge, the ovarian follicle matures, and ovulation ensues. Ten to 12 days of preovulatory estrogen stimulation is needed to trigger the maturation of a follicle in preparation for ovulation. Ovulation, or expulsion of the ovum, probably results from a proteolytic enzyme acting locally to free the ovum from the encapsulated follicle. After ovulation, the disrupted ovarian tissue returns to normal, and changes occur leading to the formation of the corpus luteum from the ruptured follicle. If implantation does not occur, and human chorionic gonadotropin (hCG) is not secreted by a conceptus, the corpus luteum rapidly recedes. If, however, implantation of a fertilized oocyte does occur, the embryo produces hCG, which will maintain the corpus luteum and progesterone production necessary for maintenance of pregnancy.1Figure 64-1 shows the sequence of development of the primary follicle and its transformation into a corpus luteum during an ovarian cycle.
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