Chapter 64. Reproductive Growth and Development in the Female Adolescent

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. The current chapter focuses on the normal anatomic and histologic changes in the major reproductive organs of female and male adolescents during puberty with specific reference to hormonal influences.

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 histologic 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. For example, estrogen requires the presence of insulin to stimulate epithelial growth and of growth hormone to affect ductal proliferation.

Developmental Anatomy and Histology

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). The first histologic changes at the onset of pubertal breast development consist of proliferation of ductal and stromal tissue and fat deposition resulting in increased volume and the visible breast bud. Lobuloalveolar growth during puberty is influenced by estrogen, progesterone, prolactin, growth hormone, and adrenal steroids. Ductal growth is primarily influenced by estrogen, growth hormone, and adrenal steroids. Maturation to the stage of lactation is mainly stimulated by prolactin and adrenal steroids. The rate of growth and size of the breasts may differ, but major inequities usually disappear with maturity. 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.

Developmental Anatomy and Histology

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. The vagina at birth resembles the mature vagina with deep cryptic rugae and folds secondary to maternal estrogenic effect. As maternal estrogen levels fall in the infant, the vaginal wall becomes dry, thin, nonelastic, and nonrugated. The vagina remains in this quiescent state until the onset of puberty. 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. Colonization with H2O2-producing lactobacilli seems to be important for vaginal microbiological health and protection against infections such as human immunodeficiency virus (HIV).2 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. Cyclic changes in histology linked to the monthly rhythmic variations in both estrogen and progesterone are not established until the ovarian cycle matures 1 to 2 years postmenarche.

Uterine Cervix

The growth and maturation of the cervix results primarily from the effects of estrogen stimulation.

Developmental Anatomy and Histology

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. Since HPV is dependent on host cell replication and differentiation for its own replication and protein transcription, areas of rapid proliferation such as found in the transformation zone are vulnerable to HPV’s effects.

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 Chlamydia trachomatis and Neisseria gonorrhoeae are also known to attach preferentially to columnar cells, which may be one of the factors associated with the epidemic rates of these sexually transmitted infections among female adolescents.

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. Recent studies have shown the importance of mucosal immune parameters of the vagina and cervix that are essential for cervical and vaginal health. These parameters include both innate and adaptive immune responses. Innate responses include natural killer cell response and toll-like receptor activation. Toll-like receptor activation is key to both innate and adaptive immune responses.6 Disruption of the integrity of the cervicovaginal epithelium with trauma and inflammatory infections with sexually transmitted infections have been linked to increased acquisition of HIV in the infected woman. In addition to causing epithelial disruption, these infections result in the recruitment of CD4 (cluster of differentiation 4) cells, which are targets of HIV infection. Systemic immune disorders, such as AIDS and lupus erythematosus, are commonly associated with increased rates of certain sexually transmitted infections such as HPV.7

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.

Developmental Anatomy and Histology

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 postmenarchal.8 Histologically, the endometrium changes little until puberty. From infancy through childhood, the endometrium consists of a thin layer of low cuboidal cells and sparse stroma with no evidence of secretory activity. The rise of estrogen at the beginning of puberty stimulates endometrial 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 endometrial 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.

Anatomy and Histology

The ovary weighs 1 g at birth and 6 g by menarche. Located within the abdomen during their embryonic development, the ovaries descend into the true pelvic cavity with early puberty. At birth, the development of the oocytes and primordial follicles is primarily complete. Recent data suggest that the ovary continues into adulthood to have the potential to produce additional ova.10,11 The oocytes peak in numbers at the fifth fetal month with about 6 million oocytes present. By puberty, approximately 300,000 remain intact. 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.

Ovarian Hormonal Cycle and Physiology

Complete maturation of the ovarian follicle requires FSH, estradiol, and LH. The main role of FSH in women is to stimulate follicular maturation and acquisition of follicular FSH and LH receptors. In women, LH stimulates production of ovarian estrogen, progesterone, and androgens and induces luteinization. In addition to the presence of the gonadotropins LH and FSH, the actual sequence of hormonal stimulation may be critical to follicle development. For example, FSH appears to stimulate initial follicle growth, resulting in estrogen production. The subsequent FSH-estrogen interaction induces further maturation and the development of LH receptors. The binding of LH to these receptors promotes progesterone secretion and complete maturation of the follicle. The midcycle LH surge appears to be responsible for ovulation (Fig. 64-1). Estradiol is the main product of the ovarian follicular granulosa cells, and progesterone is the main product of the corpus luteal granulosa cells.

Rises in FSH levels stimulate follicular estradiol production, which in turn further stimulates follicular growth and production of progressively higher levels of estrogen. The increase in both FSH and estrogen levels promotes development of LH receptors on follicular cells and induces the limited but important production of progesterone. The pituitary detects the increasing estradiol amount and at a critical level releases a surge of LH. The FSH negative feedback appears to be more sensitive than LH secretion, resulting in a decrease of FSH immediately before ovulation. The rupture of the follicle and formation of the corpus luteum occurs approximately 16 to 24 hours after LH reaches its peak. Estradiol levels then drop and progesterone levels increase. The rupture of the follicle is the actual trigger for luteinization. During this luteal phase, progesterone levels increase with a concurrent smaller increase in estradiol and estrone levels. Responding to the rising estrogen and progesterone, the LH and FSH levels begin to fall. The FSH levels begin to rise just before menstruation to induce follicular growth for the subsequent cycle.