Normal menstrual cycle

INTRODUCTION — The normal menstrual cycle is a tightly coordinated cycle of stimulatory and inhibitory effects that results in the release of a single mature oocyte from a pool of hundreds of thousands of primordial oocytes. A variety of factors contribute to the regulation of this process, including hormones and paracrine and autocrine factors that are still being identified. The cyclic changes in the major pituitary and gonadal hormones are illustrated in the figures (figure 1 and figure 2).

The definitions and physiology of the normal menstrual cycle will be discussed here. The definitions and etiology of abnormal uterine bleeding, and the detection of ovulation and ultrasound evaluation of the menstrual cycle are reviewed separately. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis", section on 'Definitions' and "Causes of female genital tract bleeding", section on 'Uterine bleeding' and "Ultrasound evaluation of the normal menstrual cycle" and "Evaluation of the menstrual cycle and timing of ovulation".)

DEFINITIONS OF NORMAL UTERINE BLEEDING (MENSTRUATION) — The four parameters used to define normal uterine bleeding are frequency, regularity, duration, and volume (table 1) [1-4]. Assessment is generally based on the patient's bleeding pattern during the previous six months and applies to patients who are not taking local or systemic medications (eg, progestin-based contraceptives with or without estrogen, gonadotropin-releasing hormone agonists or antagonists, aromatase inhibitors, selective estrogen or progesterone receptor modulators) that may directly impact gonadal steroid production or endometrial function.

●Frequency – Normal frequency is the onset of menstrual bleeding every 24 to 38 days.

●Regularity – When assessing regularity, cycle length is defined as the number of days from the start (day 1) of one period until the start (day 1) of the next period. Variation in cycle length (ie, the difference between the shortest to longest cycle) depends on age and is normal (regular) when (table 2) [3-5]:

•18 to 25 years – Cycle variation ≤9 days

•26 to 41 years – Cycle variation ≤7 days

•42 to 45 years – Cycle variation ≤9 days

For patients ages <18 and >45 years, the frequency of infrequent or unpredictable ovulation is much higher, rendering the definition of normal regularity in this population difficult.

●Duration – The normal number of bleeding days in a single menstrual period is ≤8 days [5-8].

There is no consensus regarding the lower limit of normal for the duration of menses as there are no specific pathologic entities associated with a short duration.

●Volume – Normal volume is subjective and defined as menstrual blood loss volume that does not interfere with a patient's physical, social, emotional, and/or material quality of life [9,10].

For research that involves quantitative analysis of menstrual blood loss volume (including clots), the definition of normal is ≤80 mL menstrual blood loss per cycle.

There are some variations within normal populations in the regularity and frequency of menstrual bleeding. For example, in population studies, the range of shortest to longest cycles was 2 to 20 days [1-6]. In addition, little is known about cultural, ethnic, or geographic variations since comparative large-scale studies have not been conducted [1,2].

PHASES OF THE MENSTRUAL CYCLE — The menstrual cycle is divided into two phases: follicular and luteal.

●The follicular phase begins with the onset of menses and ends on the day before the luteinizing hormone (LH) surge.

●The luteal phase begins on the day of the LH surge and ends at the onset of the next menses.

The remainder of this topic will review the hormonal, ovarian, and endometrial changes that occur during the different phases of the menstrual cycle.

Early follicular phase — The early follicular phase in humans is the time when the ovary is the least hormonally active, resulting in low serum estradiol and progesterone concentrations (figure 1). Release from the negative feedback effects of estradiol, progesterone, and probably luteal phase inhibin A results in a late luteal/early follicular phase increase in gonadotropin-releasing hormone (GnRH) pulse frequency and a subsequent increase in serum follicle-stimulating hormone (FSH) concentrations of approximately 30 percent [11]. This small increase in FSH secretion appears to be required for the recruitment of the next cohort of developing follicles, one of which will become the dominant and ultimately ovulatory follicle during that cycle [12-14].

Serum inhibin B concentrations, secreted by the recruitable pool of small follicles, are maximal and may play a role in suppressing the FSH rise at this time in the cycle (figure 3) [15]. There is also a rapid increase in luteinizing hormone (LH) pulse frequency at this time, from one pulse every four hours in the late luteal phase to one pulse every 90 minutes in the early follicular phase [16].

The early follicular phase is also associated with a unique neuroendocrine phenomenon: slowing or cessation of LH pulses during sleep that does not occur at other times of the menstrual cycle (figure 4). How this occurs is not known.

Serum anti-müllerian hormone (AMH) has been used as a potential marker of ovarian health and aging. It is secreted by small antral follicles and correlates with the total number of ovarian antral follicles. The variability of serum AMH across the menstrual cycle appears to be minimal [17]. (See "Female infertility: Evaluation", section on 'Anti-müllerian hormone' and "Ovarian development and failure (menopause) in normal women", section on 'Menopause'.)

Ovaries and endometrium — Ovarian ultrasonography has demonstrated that the ovary is quiescent in the early follicular phase, except for the occasionally visible resolving corpus luteum from the previous cycle. The endometrium is relatively indistinct during menses and then becomes a thin line once menses is complete. It is normal to see small follicles of 3 to 8 mm in diameter at this time. (See "Ultrasound evaluation of the normal menstrual cycle".)

Mid-follicular phase — The modest increase in follicle-stimulating hormone (FSH) secretion in the early follicular phase gradually stimulates folliculogenesis and estradiol production, leading to progressive growth of the cohort of follicles selected that cycle. As several follicles initially grow to the antral stage, their granulosa cells hypertrophy and divide, producing increasing serum concentrations of estradiol via FSH stimulation of aromatase and then inhibin A from the granulosa cells in the ovaries.

The increase in estradiol production feeds back negatively on the hypothalamus and pituitary, resulting in suppression of mean serum FSH and luteinizing hormone (LH) concentrations as well as the LH pulse amplitude. In comparison, the gonadotropin-releasing hormone (GnRH) pulse generator speeds up slightly to a mean LH pulse frequency of approximately one per hour (versus one per 90 minutes in the early follicular phase). GnRH stimulation is presumably due to release of negative feedback effects of progesterone from the previous luteal phase. (See "Physiology of gonadotropin-releasing hormone".)

Ovarian and endometrial changes — Within approximately seven days from the onset of menses, several 9 to 10 mm antral follicles are visible on ovarian ultrasonography. The rising serum estradiol concentrations result in proliferation of the uterine endometrium, which becomes thicker, with an increase in the number of glands and the development of a "triple stripe" pattern on ultrasound (figure 2) [18]. (See "Ultrasound evaluation of the normal menstrual cycle".)

Late follicular phase — The serum concentrations of estradiol and inhibin A increase daily during the week before ovulation due to release from the growing follicle. Serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) concentrations are falling at this time due to negative feedback effects of estradiol and perhaps other hormones released from the ovary (figure 1). As the dominant follicle is selected, FSH induces LH receptors in the ovary and increases ovarian secretion of intrauterine growth factors such as insulin-like growth factor-1 (IGF-1).

Ovarian, endometrial, and cervical mucus changes — By the late follicular phase, a single dominant follicle has been selected, while the rest of the growing cohort of follicles gradually stop developing and undergo atresia. The dominant follicle increases in size by approximately 2 mm per day until a mature size of 20 to 26 mm is reached. (See "Ultrasound evaluation of the normal menstrual cycle".)

Rising serum estradiol concentrations result in gradual thickening of the uterine endometrium and an increase in the amount and "stringiness" (spinnbarkeit) of the cervical mucus. Many people are able to detect this change in mucus character. Studies of cervical mucus samples during the menstrual cycle demonstrate a late follicular-phase peak in the mucin protein MUC5B that may be important for sperm transit to the uterus [19].

Midcycle surge and ovulation — Serum estradiol concentrations continue to rise until they reach a peak approximately one day before ovulation. Then, a unique neuroendocrine phenomenon occurs: the midcycle surge [20]. The surge represents a switch from negative feedback control of luteinizing hormone (LH) secretion by ovarian hormones (such as estradiol and progesterone) to a sudden positive feedback effect, resulting in a 10-fold increase in serum LH concentrations and a smaller rise in serum follicle-stimulating hormone (FSH) concentrations (figure 1). In addition to estrogen and progesterone, other ovarian factors contribute to the LH surge because it cannot be recreated simply by administering estrogen and a progestin in the early to mid-follicular phase to achieve serum concentrations similar to those at the midcycle [21].

At this time, the frequency of LH pulses continues to be approximately one per hour, but the amplitude of the LH pulses increases dramatically. The switch from negative to positive feedback of LH release is poorly understood. An increase in the number of pituitary gonadotropin-releasing hormone (GnRH) receptors may contribute, but there is probably no change in GnRH input to the pituitary [22].

Ovarian changes — The LH surge initiates substantial changes in the ovary. The oocyte in the dominant follicle completes its first meiotic division. In addition, the local secretion of plasminogen activator and other cytokines required for the process of ovulation is increased [23,24]. The oocyte is released from the follicle at the surface of the ovary approximately 36 hours after the LH surge. It then travels down the fallopian tube to the uterine cavity. There is a close relation of follicular rupture and oocyte release to the LH surge; as a result, measurements of serum or urine LH can be used to estimate the time of ovulation. (See "Evaluation of the menstrual cycle and timing of ovulation".)

Even before the oocyte is released, the granulosa cells surrounding it begin to luteinize and produce progesterone. Progesterone acts rapidly to slow the pulse generator so that LH pulses become less frequent by the termination of the surge.

Endometrium — The gradually increasing serum progesterone concentrations have a profound impact on the endometrial lining, leading to cessation of mitoses and "organization" of the glands [25]. This change can be detected on ultrasonography relatively soon after ovulation; the "triple stripe" image is lost, and the endometrium becomes more uniformly bright (figure 2) [18]. (See "Ultrasound evaluation of the normal menstrual cycle".)

Luteal phase — Progesterone secretion from the corpus luteum [26] results in gradually rising progesterone concentrations in the middle to late luteal phase. This leads to progressive slowing of luteinizing hormone (LH) pulses down to one pulse every four hours. Pulses of progesterone occur soon after these slow LH pulses. As a result, there can be significant excursions in serum progesterone concentrations during the luteal phase (figure 5) [27]. Inhibin A is also produced by the corpus luteum, and serum concentrations of inhibin A peak in the mid-luteal phase. Inhibin B secretion is virtually absent during the luteal phase (figure 3). Serum leptin concentrations are highest in the luteal phase [28].

In the late luteal phase, a decrease in LH secretion results in a gradual fall in progesterone and estradiol production by the corpus luteum in the absence of a fertilized oocyte. If, however, the oocyte becomes fertilized, it implants in the endometrium several days after ovulation. The early embryo begins to make chorionic gonadotropin, which maintains the corpus luteum and progesterone production.

Endometrial changes — The decline in estradiol and progesterone release from the resolving corpus luteum results sequentially in the loss of endometrial blood supply, endometrial sloughing, and the onset of menses approximately 14 days after the LH surge. Menses is a relatively imprecise marker of hormonal events in the menstrual cycle since there is considerable interindividual variability in the relationship between the onset of endometrial sloughing and the fall in serum hormone concentrations during the luteal phase (figure 2) [11].

In response to falling corpus luteum steroid production, the hypothalamic-pituitary axis is released from negative feedback and follicle-stimulating hormone (FSH) levels rise, thereby beginning the next cycle.

MENSTRUAL PRODUCTS — Menstrual products (eg, pads, tampons, cups) are discussed in our patient information section. (See "Patient education: Menstruation (The Basics)".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Menstruation (The Basics)")

SUMMARY

●Definitions – Normal menstruation is defined as (table 1) (see 'Definitions of normal uterine bleeding (menstruation)' above):

•Frequency – 24 to 38 days.

•Regularity – No more than seven to nine days difference between the shortest to longest cycles; cycle length is the number of days from the first day of one menstrual cycle to the first day of the next.

•Duration – Up to eight days; duration is the number of days of bleeding in a single menstrual period.

•Volume – Clinical definition is subjective and defined as a volume that does not interfere with a patient's physical, social, emotional, and/or material quality of life; the research definition of normal volume is ≤80 mL menstrual "blood" loss per cycle.

●Phases – The menstrual cycle is divided into two phases: follicular and luteal (figure 1), which are further characterized by specific endocrine and ultrasound findings. (See 'Phases of the menstrual cycle' above.)

•The follicular phase begins with the onset of menses and ends on the day before the luteinizing hormone (LH) surge.

•The luteal phase begins on the day of the LH surge and ends at the onset of the next menses.