Adolescent Health Care: A Practical Guide

Chapter 49

Normal Menstrual Physiology

Sari L. Kives

Judith A. Lacy

This chapter reviews normal menstrual physiology and the next several chapters discuss common abnormalities of menstrual function in adolescents.

The development of the menstrual cycle depends on the maturation of the hypothalamic-pituitary-ovarian axis that occurs during puberty. For cyclic menses to occur, there must be a coordinated sequence of events, beginning with the hypothalamic secretion of gonadotropin-releasing hormone (GnRH). In response to GnRH, the pituitary secretes follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and the ovaries secrete, estrogen, progesterone, activin, and inhibins. Ultimately, the endometrium of the uterus responds to estrogen and progesterone with stimulation and endometrial growth, as well as withdrawal. This process culminates in menses.

The menstrual cycle is under the influence of both positive and negative feedback mechanisms. In the beginning of the menstrual cycle, low levels of estradiol perpetuate a positive feedback mechanism and subsequently stimulate secretion of FSH and LH. At higher levels, estradiol and progesterone create a negative feedback effect and suppress FSH and LH, thereby preventing further follicular recruitment. Although the gonadotropins act synergistically, FSH primarily affects follicular growth and LH mainly stimulates ovarian steroid biosynthesis.

Although the trigger for menarche is unknown, hypothesized mechanisms for the onset of menses include the following:

1. A progressive decrease in the sensitivity of the hypothalamus to gonadal steroids made possible by the following:
2. A decrease in the negative feedback settings of the hypothalamus to estradiol and testosterone, resulting in higher levels of LH and FSH.
3. The rise in LH and FSH may be secondary to a central biological clock, altering GnRH response and unrelated to feedback sensitivity to gonadal steroid secretion.
4. A rise in LH secretion: During early puberty LH spikes occur only at night, in a pulsatile manner. In late puberty and adulthood, pulsatile LH secretion occurs throughout the day and night.
5. An increase in the pulsatile secretion of GnRH, both in amplitude and in frequency, leading to an increase in sex steroid secretion. Ultimately, the development of a positive feedback system allows critical levels of estradiol to trigger pulsatile secretion of GnRH and subsequently that of LH.
6. A critical body composition or percentage of body fat. There is evidence to suggest that menarche occurs at approximately 17% body fat. The maintenance or restoration of menstruation is thought to require a minimum of 22% body fat (Frisch and McArthur, 1974).

In the United States, menarche occurs in girls at an average age of approximately 12.7 years, with a range (2 standard deviations) of 11 to 15 years. In approximately two thirds of girls, menarche occurs at sexual maturity rating (SMR) 4 (Tanner pubertal stage 4).

Menarche occurs approximately 3.3 years after the start of the growth spurt, approximately 2 years after thelarche, and approximately 1.1 years after the peak height velocity. The earlier the onset of puberty (secondary sexual characteristics) the longer is the interval until the onset of menses. Additionally, females who have a late menarche will also experience a longer duration of anovulatory cycles (Emans, 2005). Menarche is followed by approximately 5 to 7 years of increasing regularity as the cycles shorten to reach the usual reproductive pattern. The greatest variability in cycle length occurs in the immediate years following the onset of menarche and those preceding the menopause (Silberstein and Merriam, 2000).

Definition of Menstrual Cycle

A menstrual cycle is defined as that period of time from the first day of menstrual period to the first day of the next menstrual flow. On the basis of current understanding, the menstrual cycle may be described by the response of the pituitary (i.e., FSH and LH levels), the ovary (follicular, ovulatory, and luteal phases), and the endometrium (proliferative and secretory phases) (Fig. 49.1).

FSH and LH are secreted in a pulsatile manner, with frequency varying between 1 and 2 hours in the follicular and luteal phases, respectively. The pulsatile spikes are higher in amplitude during the luteal phase. The pulsatile secretion of FSH and LH are secondary to the pulsatile secretion of GnRH from the hypothalamus. The pulsatile release of GnRH can be modulated by estradiol and progesterone feedback. Neurotransmitters (i.e., dopamine, norepinephrine) and endorphins (opioids) also play a role

P.672

in modulating GnRH secretion. Menstrual irregularities that occur with weight loss, stress, exercise, and drugs may be secondary to the effect of these compounds on the hypothalamus.

The physiological mechanisms of the menstrual cycle can be divided into three descriptive phases—the follicular phase, the ovulatory phase, and the luteal phase.

Follicular Phase

The duration of the follicular phase is usually 14 days, but the length is highly variable (range 7 to 22 days). This phase begins with the onset of menses and ends with ovulation. The duration of the follicular phase is the major determinant of menstrual cycle length.

1. During the end of the prior menstrual cycle, corpus luteum involution occurs, with resulting decreasing levels of estradiol and progesterone. The low levels stimulate the hypothalamic release of GnRH, which in turn increases the pituitary's release of FSH and LH.
2. FSH stimulates the recruitment of ovarian follicles.
3. At present, it is believed that LH stimulates ovarian theca cells to produce androgens, which are then converted to estrogens in the granulosa cells of the ovary under the influence of FSH (Fig. 49.2). Estradiol increases FSH binding to granulosa cell receptors, leading to amplification of the FSH effect, allowing one follicle to predominate.
4. Under the influence of estrogen, the proliferative phase of the endometrium occurs. The binding of estradiol to its receptor sites on the endometrium results in the production of growth factors that stimulate marked proliferation within the glandular and stromal compartments of the endometrium. The height of the endometrium increases from approximately 1 mm at the time of menstruation to 5 mm at the time of ovulation. The major effect of estrogen on the endometrium is that of growth. Estrogen also increases the number of estrogen and progesterone receptors in endometrial cells.
5. Estrogen causes maturation of vaginal basal cells into superficial squamous epithelial cells and the formation of watery vaginal mucus, which can be strung out (spinnbarkeit) or dried, forming a ferning pattern.
6. In response to rising estradiol levels in the middle and late follicular phase, FSH release begins to fall.

Ovulatory Phase

1. A preovulatory estradiol surge leads to a midcycle LH surge which initiates ovulation approximately 10 to 16 hours after the LH surge. An estradiol level of approximately 200 pg/mL or higher for at least 2 days is

P.673

needed to induce ovulation. A small preovulatory rise in progesterone is required to induce the FSH surge.

2. A mature follicle releases an oocyte and becomes a functioning corpus luteum.
3. At this stage there are copious, clear vaginal secretions, with maximum spinnbarkeit and a positive fern test result.

Luteal Phase

The luteal phase begins with ovulation and ends with the menstrual flow. This phase is more constant, lasting approximately 14 ± 2 days, reflecting the life of the corpus luteum.

1. The corpus luteum produces large amounts of progesterone, as well as increased levels of estrogen. Granulosa cells are exposed to low-density lipoprotein (LDL) cholesterol as a result of the invasion of blood vessels into the collapsed follicle. LDL acts as a substrate for progesterone synthesis. A progesterone serum level of >3 ng/mL is a presumptive evidence of ovulation. Rising levels of estrogen and progesterone lead to falling levels of FSH and LH.
2. Progesterone antagonizes the action of estrogen by reducing estrogen receptor sites and increasing conversion of estradiol to estrone, a less potent estrogen. Progesterone halts the growth of the endometrium and stimulates differentiation into a secretory endometrium. The secretory phase is characterized histologically by increased tortuosity of glands and spiraling of blood vessels. Secretory activity is maximal, and stromal edema occurs. The secretory endometrium is prepared for implantation.
3. Local progesterone produced by the corpus luteum suppresses follicular development in the ipsilateral ovary so that ovulation in the following month usually occurs in the contralateral ovary.
4. The cervical mucus becomes thick during the luteal phase, owing to the influence of progesterone, and no ferning or spinnbarkeit occurs.
5. Unless there is fertilization with subsequent production of human chorionic gonadotropin, the corpus luteum involutes after approximately 10 to 12 days. Sloughing of the endometrium occurs secondary to a loss both of estrogen and of supportive progesterone. Local prostaglandins cause vasoconstriction and uterine contractions.
6. The decreased levels of estrogen and progesterone lead to increased levels of FSH and LH, providing the positive feedback loop required to initiate another menstrual cycle.

Conclusion

Menarche is that time in the female life cycle denoting the beginning of menses and the commencement of orderly cyclic hormonal changes. Normal menstrual cycles require an orchestrated sequence of events to occur between the hypothalamus, pituitary, ovaries, and the endometrium. Abnormal menstrual cycles are not uncommon and require appropriate clinical assessment and evaluation to determine etiology. Common menstrual disorders experienced by adolescents, including dysmenorrhea, dysfunctional uterine bleeding, and amenorrhea will be discussed in the following chapters.

Web Sites

http://www.fda.gov/fdac/reprints/ots_mens.html. U.S. Food and Drug Administration Web site for teenagers, abridged from FDA Consumer, December, 1993. Provides general information on menstruation for teens.

http://www.youngwomenshealth.org/menstrual.html. Boston Children's Hospital site, guide to puberty and menses.

References and Additional Readings

Emans SJ. Endocrine abnormalities and hirsutism. In: Emans SJ, Laufer MR, Goldstein DP, eds. Pediatric and adolescent gynecology. Philadelphia: Lippincott Williams & Wilkins; 2005.

Filicori M, Santoro N, Merriam GR, et al. Characteristics of the physiological pattern of episodic gonadotropin secretion throughout the human menstrual cycle. J Clin Endocrinol Metab 1986;6:1136.

Frisch RE, McArthur JW. Menstrual cycles: fatness as a determinant of minimum weight necessary for their maintenance or onset. Science 1974;53:384.

Fritz MA, Speroff L. The endocrinology of the menstrual cycle: the interaction of the folliculogenesis and neuroendocrine mechanisms. Fertil Steril 1982;38:509.

Gobelsmann U. The menstrual cycle. In: Mishell DR Jr, Davajan V, eds. Infertility, contraception, and reproductive endocrinology. Oradell, NJ: Medical Economics Books; 1986.

Gobelsmann U, Mishell DR. The menstrual cycle. In: Mishell DR Jr, Davajan V, Lobo A, eds. Infertility, contraception, and reproductive endocrinology, 3rd ed. Boston: Blackwell Science; 1991.

Hermann-Giddens ME, Slora EJ, Wasserman RC, et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the pediatric research in office settings network. Pediatrics 1997;99:505.

Iglesias EA, Coupey SM. Menstrual cycle abnormalities: diagnosis and management. Female reproductive health; adolescent medicine. State Art Rev 1999;10:255–273.

Lobo RA, Paulson RJ, Mishell DR Jr, et al., eds. Textbook of infertility, contraception, and reproductive endocrinology, 4th ed. Malden, MA: Blackwell Science; 1997.

Mandel D, Zimlichman E, Mimouni FB, et al. Age at menarche and body mass index: a population study. J Pediatr Endocrinol 2004;17:1507.

Neinstein LS. Menstrual disorders. Semin Fam Med 1981;2:184.

Neinstein LS. Menstrual problems in adolescents. Med Clin North Am 1990;74:1181.

Rosenfield RL, Barnes RB. Menstrual disorders in adolescence. Endocrinol Metab Clin North Am 1993;22:491.

Silberstein SD, Merriam GR. Physiology of the menstrual cycle. Cephalalgia 2000;20:148.

Speroff L, Glass RH, Kase NG, eds. Clinical gynecologic endocrinology and infertility, 6th ed. Baltimore: Williams & Wilkins; 1999.

Vuorento T, Huhtaniemi I. Daily levels of salivary progesterone during menstrual cycle in adolescent girls. Fertil Steril 1992; 58:685.