Adolescence: maturation of menstruation and ovulation

In childhood, usually between ages 6 and 9, the neuroendocrine and hormonal changes that eventually lead to menarche and menstrual cycling are initiated. The pulses of LH that have been low and almost imperceptible become increased in size, slower, and more adult-like but only during sleep. By menarche the larger LH peaks of adulthood are also present during the day.

The age at menarche varies in different populations but it is accepted to be ages 11–13 for the majority in the advantaged world and somewhat later in other countries. First cycles are usually unpredictable, occasionally too close together, and often too far apart (longer than 45 days) with a mean of 33 days (American College of Obstetricians and Gynecologists, 2015; van Hooff et al., 1998) (Figure 3.3).

Figure 3.3   Bar graph showing cycle lengths (open) and luteal phase lengths (solid) with ovulatory changes that are typical across the menstruating lifecycle. Drawn by D. Kalidasan from a sketch by Prior.

In addition, adolescents’ first cycles are usually anovulatory, but by the end of the first year may develop ovulation with short luteal phases; within 5 years cycles will be intermittently normally ovulatory (Apter, Viinikka, & Vihko, 1978) (Figure 3.3). In prospective data, Vollman (1977) used a quantitative mean temperature method to document ovulation/luteal phase length (later validated by Prior, Vigna, Schulzer, Hall, & Bonen, 1990), and discovered that it took about 12 years following menarche before the most consistent, normal ovulation occurred.

Age at menarche is associated with various health and disease characteristics. Early menarche (ages 11 or earlier, where the mean was 12.9 years), in a Canada-wide adolescent-to-adult population study with measured anthropomorphic data, was related to a significantly higher adult body mass index (BMI) with obesity in those with the earliest menarche ages (Harris, Prior, & Koehoorn, 2008). Other populations have shown the same pattern (Ahn et al., 2013), including that there is a 9% decreased risk for type 2 diabetes mellitus per year later age at menarche (Lakshman et al., 2008). Early menarche (in Great Britain characterized as <12 years, mean 13) was associated with a 20% increased risk for cardiovascular diseases and cancers plus overall mortality ( Lakshman et al., 2009); a 10% increased all-cause mortality with early menarche (ages 10–11, where the mean was 14) was confirmed by a 37-year longitudinal, whole-population Norwegian study (Jacobsen, Heuch, & Kvale, 2007). A later age at menarche (older than 15) was associated with decreased all-cause mortality in a European population-based study (Merritt et al., 2015).

The largest gain in height occurs around the time of menarche, and hip bone mineral density reaches its peak during ages 16–19 based on prospective, population data (Berger et al., 2010). There is evidence that progesterone (and thus the development of ovulation), as well as estrogen, is responsible for breast growth and transformation (Prior, Vigna, & Watson, 1989).

Premenopause: the peak of menstruating life and fertility

The normal premenopausal menstrual cycle length of 21–35 days (Abraham, 1978) has a population average of 27–29 days. Flow normally lasts 2–6 days. Normal ovulation is present in about two thirds of all normal-length menstrual cycles in women ages 20–49, mean age 42 (Prior, Naess, Langhammer, & Forsmo, 2015).

Normal cycle lengths between 21 and 35 days are usual from the early 20s until the mid-30s or whenever perimenopause begins (Figure 3.3). Flow of 2–6 days is associated with 30–60 milliliters (ml) of blood loss, which requires 6–12 soaked normal-sized menstrual management products (each holding ~5 ml or a teaspoon) (Hallberg, Hogdahl, Nillson, & Rybo, 1966). However, menorrhagia, which almost always causes iron deficiency anemia, is associated with blood loss of >80 ml/period (>16 soaked products; Hallberg et al., 1966). Heavy flow is characterized by needing to change (often large or “maxi” sized) sanitary products every 1–2 hours (or empty a 30 ml menstrual cup every 8–12 hours), clotting, and often increased cramping. Although premenstrual symptoms may occur during the premenopausal years and be managed by increasing exercise (Prior, Vigna, & Alojado, 1986), intense symptoms (ascertained in a population-based cohort with its purpose masked) are quite rare (Ramcharan, Love, Frick, & Goldfien, 1992).

Women’s usual way of assessing whether they ovulate is to rely on “regular cycles”; some may also describe noticing “fertile mucus” at mid-cycle (i.e., several days of clear, egg-white type, stretchy secretion with a maximal thread-stretch of over 3 centimeters). This mucus is specific for cervical gland secretion in response to high mid-cycle estradiol levels (Figure 3.1). However, a mid-cycle estrogen peak (noted by the stretchy mucus) or an LH peak (documented with a urine stick) does not mean that those normal pre-ovulatory signals have actually triggered egg release and progesterone (Brown, 2011). Nor does it mean that, if ovulation occurs, the luteal phase length is long enough for implantation and thus fertility. Quantitative basal temperature [QBT] data require 10-day luteal phases (Vollman, 1977) or 11–12 days by urine LH data (Cole, Ladner, & Byrn, 2009) to define a fertile cycle.

Can women perceive an ovulatory cycle because they feel different in the luteal phase? Some believe that non-troublesome premenstrual experiences (called “molimina”) accurately indicate ovulation (Magyar, Boyers, Marshall, & Abraham, 1979). However, attempts to validate this have so far failed (Goshtasebi et al., 2017). As progesterone raises the core temperature by ~0.2 degrees Celsius (Landau, Bergenstal, Lugibihl, & Kascht, 1955) and this is reliably measured first thing in the morning, temperature testing seems ideal. However, basal temperature data have been shown to be inaccurate (Bauman, 1981). Quantitative basal temperature (QBT) uses a 3-day running average and assesses means during the follicular and luteal phases. The temperature shift day correlates highly with (r=~0.9) but lags 1–3 days behind the serum LH peak (Prior et al., 1990b). The mean temperature QBT (all of cycles’ temperatures added together and divided by the number of days of data) is simpler. The luteal phase begins when the actual temperature rises above and stays above the mean temperature and lasts until the start of the next flow (CEMCOR, 2019; Prior et al., 1990b).

There is a growing appreciation that the (estrogen-only) follicular and the (progesterone-estrogen) luteal phases of the menstrual cycle differ in physiological and metabolic characteristics. Healthy, weight-stable younger women eat about 300 kilo-calories more during the luteal phase (Barr et al., 1995), likely because of energy requirements of ovulation-related elevated temperatures. Insulin resistance is increased during the late follicular phase, and estrogen’s influence is stronger than progesterone’s and insulin resistance is highest in anovulatory cycles (Yeung et al., 2010). In a study of 60 healthy, normal-weight, non-smoking women, daily self-report of feelings of frustration, depression, and anxiety were not higher during the luteal than the follicular phase nor related to hormone levels (Harvey, Hitchcock, & Prior, 2009). Sixty-six initially ovulatory women recorded QBT, exercise, and menstrual cycles and reported fluid retention as greatest on the first day of flow (White, Hitchcock, Vigna, & Prior, 2011). Oxidative stress marker levels have been shown to be higher during follicular than luteal phases and most strongly related to higher estrogen (Schisterman et al., 2010).

Perimenopause: the unpredictable and chaotic end of menstrual cycles

An estrogen/progesterone imbalance with estrogen dominance characterizes perimenopause (Santoro, Rosenberg, Adel, & Skurnick, 1996) with loss of the usual feedback suppression of estrogen by higher endogenous/exogenous estrogen levels (Weiss, Skurnick, Goldsmith, Santoro, & Park, 2004). Beyond the mid-30s and usually in the mid-40s cycles stay “regular” but gradually become shorter until they often average ≤25 days in very early perimenopause (Prior, Seifert-Klauss, & Hale, 2012) (Figure 3.3). Cycles then become slightly or definitely irregular and unpredictable (early menopause transition) before the first skipped menstruation that signals the late menopause transition. Perimenopause is the normal mid-life transition from premenopausal menstrual cycles to menopause; it may be perceived only for a short time if mild, but women who are highly symptomatic often experience perimenopausal changes/symptoms for over 10 years (Freeman, Sammel, Lin, Liu, & Gracia, 2011; Prior et al., 2012). A comprehensive older survey of the experiences of women in different reproductive life phases showed that adolescent and perimenopausal women shared many physiological and psychosocial experiences (Neugarten & Kraines, 1965), perhaps because both were experiencing major social status as well as physiological transitions.

The usual age at onset of unpredictable or irregular cycles (early menopause transition) (Harlow et al., 2012) (Figure 3.4) is 46–48 years in population data from the USA (McKinlay, Brambilla, & Posner, 1992).

Figure 3.4   The four phases of perimenopause including very early perimenopause when women’s experiences and hormones have changed but before the consensus (Harlow et al., 2012) says that the “menopause transition” has begun. Reprinted with permission from Prior et al., 2012.

Defining the onset of perimenopause by menstrual cycle changes, however, does women a disservice because the hormonal changes of perimenopause (higher estradiol and lower progesterone levels) have already begun despite maintaining regular menstruation (Moen, Kahn, Bjerve, & Halvorsen, 2004; Prior, 1998, 2006; Santoro et al., 1996).

Normal perimenopause may begin as early as age 35 and still end with a normal menopause (defined as 1 year beyond the last flow) at 40–45 years. Although about 80% of women have few symptoms in perimenopause, approximately one third of women seeking medical help report very heavy flow (Kaufert, 1986). Other women become troubled by mid-sleep awakening and night sweats that tend to occur cyclically around flow (Hale, Hitchcock, Williams, Vigna, & Prior, 2003). As midlife women are often most symptomatic before their menstrual periods become irregular, it is useful to recognize those with night sweats, sleep disturbances, and shorter cycles as entering perimenopause (Prior, 2005). Other experience changes that may also indicate perimenopause onset while flow is regular are worsening cramps, heavy flow, new/worsening migraines, breast tenderness/lumpiness, premenstrual symptoms, and weight gain despite little change in diet/exercise (Prior, 2005). Any three of the nine above-listed experience changes can be used to make a diagnosis of very early perimenopause (Figure 3.4) (Prior, 2005).

Following a time of irregular cycles (during which heavy flow may still occur and daytime hot flushes may begin) (Figure 3.4) women will then experience a skipped period (or cycle length >60 days) that marks the beginning of the late menopause transition (Harlow et al., 2012). This may be followed within 1–2 years by the final menstruation. The last phase of perimenopause is very late perimenopause, which characterizes the final year of menstrual life. During this year, breast tenderness and cramps have usually gone (unless they are predicting flow) and often vasomotor symptoms (VMS) reach their peak lifetime intensity (Dennerstein, Dudley, Hopper, Guthrie, & Burger, 2000).

An individual woman’s path through perimenopause is marked by considerable variation rather than a predictable progression (Kaufert, Gilbert, & Tate, 1987; Mansfield, Carey, Anderson, Barsom, & Koch, 2004). The further women move from the onset of perimenopause, according to Australian population-based data, the less symptomatic they become except that some experience lower libido, more VMS (both day and night), and more frequent headaches (Dennerstein et al., 2000). Perimenopause may, and often does, last 5–10 years.

Symptomatic perimenopause is currently commonly treated with combined hormonal contraceptives (CHC) or menopausal-like ovarian hormone therapy (OHT). However, if estrogen levels are high and poorly suppressible (Prior, 1998), more estrogen is unlikely to help. One study (Casper, Dodin, Reid, & Study Investigators, 1997) showed no significant changes from placebo or CHC related to quality of life, heavy flow, or hot flushes. Perimenopausal heavy flow, in my clinical experience, improves with ibuprofen (200–400 mg with each meal on every day of flooding menstruation) plus oral micronized progesterone in a physiological luteal phase dose of 300 mg at bedtime daily (Simon et al., 1993). In perimenopausal heavy flow, progesterone needs to be given for 3 months continuously to overcome the cumulative effects of higher estrogen levels, rather than cyclically as in premenopausal women (Prior, 1997). Another effective non-surgical option is the levonorgestrel-releasing IUD (Lethaby, Hussain, Rishworth, & Rees, 2015). Only if there is documented endometrial cancer should hysterectomy be used to “treat” perimenopausal menorrhagia. The natural history of mid-life heavy flow is that it improves the longer a woman is in perimenopause.

Cramps also tend to increase in perimenopause. Ibuprofen, or another non-steroidal anti-inflammatory agent, initially and then “on demand” also works in this situation. A recent randomized controlled trial (RCT) of oral micronized progesterone for perimenopausal VMS showed a daily diary trend to overall improvement, but women perceived significantly improved night sweats in both early and later perimenopause (Prior et al., 2018). It is well documented in RCTs that 300 mg of micronized progesterone at bedtime improves sleep (Caufriez, Leproult, L’hermite-Baleriaux, Kerkhofs, & Copinschi, 2011; Hitchcock & Prior, 2012; Schussler et al., 2008) and that this is progesterone’s major “side effect.”

Menopause: a new flow-less life phase

Menopause refers to the life phase that begins for a woman who has been 12 months without flow. (The term “postmenopause” should no longer be used because it refers to the now-obsolete definition of “menopause” as the literal last menstrual flow.) The normal age at menopause is officially 40–58 years, with an average age of 49–52, depending on the country. Those few who become menopausal at age 45 or younger may be at higher risk for cardiovascular diseases as well as osteoporosis. The perimenopausal woman who had a difficult time will, in general, be less symptomatic in menopause (although she may have VMS for several more years depending on how early in perimenopause they began) (Freeman et al., 2011).

The 12-month landmark is a statistical “fact”: 90% of women aged 45 years or older at menopause onset will not experience a further flow (Wallace, Sherman, Bean, Treloar, & Schlabaugh, 1979). That means that 10% of women will bleed again, and as many as 20% of women younger than 45 at menopause may have flow after 12 months of amenorrhea. Asymptomatic menopausal bleeding (in women not taking OHT) is strongly associated with endometrial cancer (Kaaks, Lukanova, & Kurzer, 2002). Women experiencing flow after amenorrhea for 12 months will usually be scheduled for endometrial biopsies to exclude cancer. If women describe cramp-like pelvic pain, sore breasts, nausea, or bloating before flow, they are experiencing a normal flow, as all of those are signs of the higher estrogen levels that triggered the extra menstrual period. Unfortunately for them, the “12-month clock” then starts all over again. Only if they have further flow, within 3 years of the last flow, with no preceding symptoms, should they be investigated for endometrial cancer.