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The menopausal transition and you

The menopausal transition & you
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Menopause – A Natural Life Transition

A universal experience in aging women, menopause is a biologic event that has attained high visibility as the postwar baby boomers began reaching this milestone at the close of the last millennium. Clinically speaking, menopause signifies the permanent cessation of menstruation and the end of a reproductive era. It is the culmination of some 50 years of reproductive aging — a continual process that unfolds from birth through ovarian aging to menopausal transition (MT) and post-menopause.
 
Yet, somehow, the common misconception persists that menopause should be feared and treated as if it were a disease. It is nothing more than a natural life transition. In recent years, there is a new understanding of how to approach menopause. According to many experts, taking a proactive approach to menopause can result in a relatively smooth, and even positive, transition.
 
A result of aging changes in the ovary and in hypothalamic-pituitary-ovarian (e.g., HPO) axis function,(1) the menopausal transition (MT) encompasses a period of dynamic changes in reproductive and non-reproductive tissues. MT is known to play a major role in the etiology of symptoms such as hot flashes, night sweats, uterine bleeding problems, and vulvovaginal atrophy (2). Mood changes (3), sleep disturbances (4), and sexual dysfunction (5) also are common and may be due to the hormonal imbalances experienced during this transition period.
 

Menopausal transition defines a period of profound physical and psychological change for a woman – but it also the biggest opportunity for personal growth and empowerment.

To appreciate the nuances behind this transition, it is therefore important to understand what it entails. In the following paragraphs, I will attempt to highlight the salient points of the MT from both physiological and symptomological view points, allowing you to identify the relative stage you are in and be able to pro-actively implement strategies – especially if considering bioidentical hormone replacement therapy (BHRT) – that will facilitate your transition into menopause.
 

The reproductive cycle in women

As defined by the Stages of Reproductive Aging Workshop (STRAW) held in July 2001, the menopausal transition (MT) begins with variations in menstrual cycle length and a continuous rise in follicle-stimulating hormone (FSH), and ends with the final menstrual period, confirmed only when followed by 12 months of missed menstrual periods (6). The peri-menopause, which literally means “about or around the menopause,” begins at the same time as the MT and ends 1 year after the final menstrual period (see Fig. 1). The median age at the final menstrual period currently stands at 51.4 years (7).
 


Fig. 1 - Stages of normal reproductive cycle in women.The stages in relation to the final menstrual period (FMP), defined as Stage 0. Stage –5: the early reproductive stage. Stage –4: the peak reproductive stage. Stage –3: the late reproductive stage. Stage –2: the early menopausal transition. Stage –1: the late menopausal transition. Stage +1a: the first year after the final menstrual period. Stage +1b: years 2 to 5 after menopause. Stage +2: the later postmenopausal years (Reprinted with permission from 6).
 
Below are highlights that define the menopause transition (MT) stages:
  • STAGE -2 (Early MT) − Previously regular menstrual cycles become more variable and cycle length changes by 7 days or more.
  • STAGE -1 (Late MT) − Characterized by two or more missed menstrual periods, at least one menstrual cycle of 60 days or more, and an FSH level greater than 40 IU/L (8).

 
In retrospect, menopause is determined after 12 months of amenorrhea (6, 9). For women with at least one menstrual cycle lasting 60 days or more, the average time to menopause is 2.6 to 3.3 years (10). For women over the age of 45 who haven’t had a menstrual period for a year, there is a 90% chance that they will not have another spontaneous menstrual period (11). Smoking alters the ovarian aging process, advancing the age of menopause by as much as 2 years (12).
 

Hormonal changes in the menopausal transition – Role of ‘ovarian aging’

During the MT, secretion of reproductive hormones such as estrogen, progesterone and testosterone was thought to decline in a linear fashion, but these have since been shown to fluctuate widely. Some of the hormonal highlights are noted below:

  • Studies in large cohorts of women have demonstrated that circulating FSH concentrations increase continuously during the MT (13-15).
  • The continuous rise in FSH is due to a decrease in ovarian Inhibin B secretion rather than to a decrease in estradiol production (15-17).
  • In perimenopausal women, estradiol production fluctuates erratically with FSH levels and can reach higher concentrations than those observed in women under 35 years of age (18, 19).
  • Estradiol levels generally do not decrease significantly until late in the MT (Stage -1) (19, 20).
  • Despite continuing regular cyclic menstruation, progesterone levels during the early MT (Stage -2) are lower than in women of mid-reproductive age and vary inversely with body mass index or BMI (15). In other words, the higher your BMI, the lower your progesterone levels.
  • Women in the late MT (Stage -1) show impaired maturation of the ovarian follicle and an increasing incidence of anovulation, compared to women of mid-reproductive age (17).
  • Moreover, testosterone levels do not vary much during the MT (14).

 
The gradual decline in ovarian estrogen production in the years prior to the complete cessation of menstruation (the menopause) is the direct result of ‘ovarian aging’ (see tab) and is largely dependent on three factors (13-15):

  • The number of remaining follicles.
  • The number of recruitable follicles in each ovarian cycle, and
  • The proportion of follicles that reach adequate maturity prior to ovulation.

 

Each woman receives an endowment of oocytes during fetal development. At the fourth month of fetal development, the ovaries contain some 6–7 million oocytes surrounded by a layer of flat Granulosa cells to form the primordial follicle pool (see Fig. 2) (21-23).
 

Fig. 2. Ovarian aging
Fig. 2. Changes in ovarian follicle reserve with increasing female age in relation to the hypothalamic-pituitary ovary system

 
At any particular age, the vast majority (>99%) of oocytes in the ovary are present as these non-growing primordial follicles (NGF). Due to a rapid loss of the great majority of the primordial follicles in the second half of fetal life, at birth only 1–2 million primordial follicles remain (24). After birth, this high rate of follicle loss slows down somewhat, so that at menarche at least 300,000 to 400,000 NGFs remain (22). During the reproductive years, the continued and gradually accelerated decline will cause numbers to have dropped below 1,000 at the time of menopause (Fig. 3) (23, 25).
 
Fig. 3. NGF model
Fig. 3. Model estimating the NGF population from conception to menopause.

 
Therefore, a defective follicular phase may result in fewer Granulosa cells being generated and less effective synthesis of estradiol per growing follicle, less Inhibin production, and then reduced negative feedback on FSH signaling – hence, the gradual increase in FSH from the mid 40s onward. As a result, more follicles are recruited into a particular cycle which can collectively produce even higher levels of serum estradiol in the years leading to menopause. In fact, near menopause, it is not surprising to see estrogen levels rise very high (nearly twice what is seen in normal menstrual cycle) and then drop very rapidly (from 700 to 30 pg/mL) within 2 or 3 days.
 
Eventually, the dwindling number of oocytes (e.g., ovulation) will also lead to a rapid loss of Progesterone production from the ovaries – the major source of these hormones in the body. This coupled with the fact that beginning in peri-menopause and continuing throughout menopause, the production of progesterone tends to decline more rapidly than that of estrogen (26), offsets the normal progesterone to estrogen balance, favoring excess estrogen and predisposing women towards a condition known as estrogen dominance.
 

Putting it all together

Some of you may be thinking this is above your heads and too geeky…don’t worry! Here’s how it all ties together:

  • Fixed oocyte pool – Every woman is born with a FIXED pool of oocytes (1-2 million), each surrounded by layers of specialized cells that comprise the follicle (22-25).
  • Oocyte quantity – The reproductive aging or decay is thought to be dominated by a decrease in the quantity of oocytes. After birth, follicle loss continues through menarche (~11 yrs of age), by which time a woman has at least 300,000 to 400,000 follicles remaining.
  • Oocyte quality – Along with the decrease in follicle number, oocyte quality is also compromised with age (at least after the age of 31 yr when fertility gradually decreases).
  • Low oocyte means low sex hormones – Since ovaries are the primary sites for the manufacturing of both progesterone and estradiol, then the decay in both oocyte quantity and quality compromises production of these hormones as a woman ages (time does its thing).

 

…But, wait! What causes ovarian aging?

While on the outset, the process of ovarian aging have a lot of what in the lingo we call ‘fixed variables’ that seem to be ‘left to chance’ and as such lie outside of our direct control (e.g., fixed number of oocytes at birth, rate of decay and loss in quantity and quality of oocytes, etc.), Mother Nature has not left us helpless.
 
To identify what these strategies may be, we need to gain an appreciation of the underlying causes that compromise quantity as well as quality of an oocyte. And while you may not be able to control the number of oocytes that Nature has bestowed upon you at birth, by understanding the causative factors that affect the process may help you implement strategies to slowdown the rate of decay and loss and extend the lifespan of her ovaries and preserve hormonal balance and homeostasis.
 
More and more studies show that the loss of oocyte quality is believed to be due to an increase in defective genetic events, especially as a woman ages (27–29). Underlying mechanisms may involve differences between cells at the time of formation during the woman’s time as a fetus, accumulated damage of oocytes in the course of a woman’s life (think DNA mutations, etc.), or age-related changes – such as oxidative damage and stress, inflammation – in the quality of the Granulosa cells surrounding the oocyte (30, 31).
 
With today’s fast paced and stressful lifestyle, we put additional insults to injury, exasperating an already compromised process and putting us on right on track to an accelerated head on collision with destiny. While it is never too late to turn the ship around, by the time many of us come to this realization and wake up, it’s the 11th hour and we are staring destiny in its eyes. Instead, we should be looking at addressing the root cause early on and implementing strategies to prevent ovarian aging early in your 20s, 30s and 40s, while it’s easier to maneuver the machine and and slow its inevitable rendezvous with Destiny.
 
In future posts, I will explore facets related to aging gracefully and slowing the process of ovarian aging and degradation. We will also discuss estrogen dominance, the roles of progesterone and estrogen in cellular signaling and various other aspects of hormonal health. Stay tuned!
 
Cheers,
Robert

 


References
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