repro aging

Benha University Hospital

Delta (Mansura) & Benha Fertility Centers

Email:elnashar1953@yahoo.com

•While there is a useful staging system for puberty

(Tanner/Marshall system), a similar staging system for late

reproductive function has not been developed.

•Confusion & duplication in the nomenclature of the reproductive aging e.g. climactric, perimenopause

•The American Society for Reproductive Medicine (ASRM)

•The National Institute on Aging (NIA)

•The North American Menopause Society (NAMS)

Cosponsored a workshop to

•develop a relevant & useful staging system

•revise the nomenclature

DefinitionAging: The natural progression of changes in structure and function that occur with the passage of time in the absence of known disease.

Reproductive aging:•A natural process that begins at birth and proceeds as a continuum. •It is a process and not an event, and the end (menopause) is much easier to define than the beginning. Chronological age is a very poor indicator of reproductive aging.

Etiology•Oocyte depletion in the ovary. •Reproductive aging consists of a steady loss of oocytes through atresia or ovulation, which does not necessarily occur at a constant rate. •The relatively wide age range (42–58 years) for menopause in normal women indicate that either - Wide variation in number of follicles at birth or -Wide variation in the rate of oocyte loss

The workshop concentrated on developing a staging system for all healthy women who age spontaneously to a natural menopause. This staging system is not applied in women who smoke cigarettes, those at the extremes of body weight (body mass index 18 kg/m 2 or 30 kg/m 2), those who do heavy aerobic exercise 10 h/wk), those with chronic menstrual cycle irregularity, those who have had a hysterectomy, or those who have abnormal uterine (e.g., fibroids) or ovarian anatomy (e.g., endometrioma).

The purpose of a staging system To identify what point a given woman has reached in the process of reproductive aging. However, not all healthy women will follow this pattern. While most normal women will progress from one stage to the next, some will “see-saw” between stages or skip a stage altogether.

The anchor for the staging system is the final menstrual period (FMP). The staging system has 7 stages; 5precede and 2 follow the final menstrual period. Stages -5 to -3 encompass the reproductive interval; Stages -2 and -1 are the menopausal transition; and Stages +1 and +2 are the postmenopause.

After menarche (entry into stage -5) it usually takes several years for regular menstrual cycles to become established. Menstrual periods should then occur every 21 to 35 days for a number of years ( stages -4 & -3).

There is no demarcation between stages -5 to -3, since fertility increases & decreases gradually over many years.

•A woman’s peak fertility occurs in her mid- to late twenties, after which it progressively decreases until menopause (stage -4 to -1). •Loss of fertility is the first sign of reproductive aging that precedes the Monotropic increase in FSH and Changes in menstrual cyclicity.

•An elevated FSH level is the first measurable sign of reproductive aging. This initial elevation in FSH level is most prominent in the early follicular phase of the cycle; a single venous blood sample should be obtained between cycle days 2 and 5 and subsequently assayed for FSH and estradiol.

Interpretation:-The initial elevation in the late reproductive stage -3 is subtle; while clinicians often use 10 mIU/mL as the cutoff value. In the research setting it would be best to determine the actual level for a particular laboratory in a young control sample from stage -4 (peak reproductive time). An elevated FSH level would be an early follicular phase level that exceeds 2 SDs of the mean level for a sample of normal women of peak reproductive age (25–30 years).

-An elevated FSH level in a single cycle is significant and is sufficient to categorize a woman as stage -3; an elevated level does not need to be repeated. -However, a normal FSH level in a 40- to 45-year-old woman with regular cycles {will be elevated in a preceding or subsequent cycle about 30% of the time}. Therefore, in this group, it is recommended that FSH be measured a second time if the first value is normal

-FSH level should only be interpreted in the context of a simultaneously measured E2.In the late reproductive stage (stage -3), E2 level in the early follicular phase is either normal or elevated. If it is elevated, it can suppress what otherwise would be an elevated FSH level An E2 level 80 pg/ml is often considered to be elevated.

MenopauseThe anchor point that is defined after 12 months of amenorrhea following the FMP (Retrospective diagnosis), which reflects a near complete but natural decrease in ovarian hormone secretion.

Menopausal transition (MT): Stage -2 (early) and -1 (late) The MT begins with variation in menstrual cycle length in a woman who has a monotropic FSH rise &ends with the FMP

The early MT (stage -2):

Menstrual cycles remain regular, but the duration changes by 7 days or more.

The late MT (stage-1):

2 or more skipped menstrual periods & at least one intermenstrual interval of 60 days or more.

•Perimenopause: Literally means “about or around the menopause.” It begins at the same time as the MT i.e. with stage -2 and ends 12 months after the FMP. •The climacteric is a vague term that used synonymously with perimenopause.

The terms perimenopause and climacteric should be used only with patients and in the

lay press and not in scientific papers.

Endocrine changes in MT:1. FSH levels gradually increase throughout MT, but levels vary greatly and it would be difficult to identify meaningful cut-off levels for stages -3 to -1. The increase in FSH early in MT is due to increased negative feedback effects on the hypothalamus & pituitary. These effects may be reduced because of a decrease in an ovarian inhibin factor rather than E2, as previously believed.

However, FSH levels can vary from cycle to cycle & can be falsely reassuring if they are low.

The ability of an FSH level to predict menopause in any individual woman is low (Shilder et al, 1989), particularly if she is under the age of 45.

2. Recent investigations suggest that a progressive, linear decline in estrogen secretion does not occur during the MT. In MT stage, the elevated FSH levels may lead to increased E2 production greater than seen in women under the age of 35 years (Santro et al, 1996). During the early stages of the MT, women generally do not have evidence of decreased E2 until they are within several years of their final menstrual period (Burger et al,1995).

3. Inhibin & activin:Inhibins are a class of proteins produced by the Sertoli & granulosa cells that inhibit pituitary FSH secretion. When the B subunits of inhibin combine they form activins, a related class of proteins that stimulate release of FSH from the pituitary.Follicular phase inhibin B is decreased in the early MT, concomitant with the rise in FSH (Burger et al, 1999). As the transition progresses, luteal phase inhibin A decline, as a later event. Activin A is elevated in MT stage *(Santoro et al,1999).

A combination of decreased inhibin A & B & increased activin may favor greater output of FSH in the absence of any decrease (& perhaps an increase) in E2 production

Symptoms of MTsymptoms of reproductive aging differ by race, ethnicity, culture, geographic region, and socioeconomic status. Symptomatic women with cycle irregularity can be clinically diagnosed as entering the MT without extensive laboratory testing. However, symptoms may be associated with multiple disorders, & testing to exclude hypothyroidism or depression may be warranted, as these conditions may occur during MT. Some women start to experience various symptoms during the late reproductive phase (stage -3), including vasomotor symptoms, breast tenderness, insomnia, migraines, and premenstrual dysphoria. In addition, genital atrophic symptoms and problems in sexual function can occur in the late menopausal transition and beyond. Vasomotor symptoms are the most frequent and prominent of the menopausal symptoms; women in stages -1 and +1 frequently experience onset or increased intensity of such symptoms.

Ovarian sonography in MT1. The number of antral follicle (2–10 mm) -Does not vary over the menstrual cycle

-Correlates well with chronological age-Before the age of 37 years, the antral

follicle count showed a mean yearly decline of 4.8%, compared with 11.7% thereafter (Scheffer et al,1999).

-Clearly related to reproductive age and reflect the size of the remaining primordial follicle pool.

2. Ovarian volume:•A strong direct relationship between ovarian volume and the number of primordial follicles remaining in the ovaries. •Follicle decline with ageWallace & Kelsey (Drs of Computer Sciences), developed a technique for measuring a woman’s

‘bioclock’ (Hum Rep, 2004). They applied mathematical and computer models/analysis2 to find out the follicle

population decline for women entering the menopause early or late

•The measurement of ovarian volume by TVS will enable 1. An accurate prediction of the age of menopause and hence a woman’s reproductive age. 2. Estimate accurately how many follicles are left and therefore what is the woman’s ‘reproductive age.. •Assisted conception, •Treatment for childhood cancer and •women who may want to delay a family for personal or professional reasons.

Stage +1 (early) postmenopausedefined as 5 years since the FMP. Stage +1 was further subdivided into segment “a”, the first 12 months after the FMP, and segment “b”, the next 4 years.

Stage +2 (late postmenopause) has a definite beginning but its duration varies, since it ends with death.

1. Stages of reproductive aging are seven: Five stages precede and two follow the final menstrual period. Stages -5 to -3 encompass the reproductive interval; Stages -2 and -1 are the menopausal transition; and Stages +1 and +2 are the postmenopause.

2. The reproductive staging system is a distinct improvement in reproductive health.

3. These definitions are currently the best description of reproductive aging but are subject to modification as more knowledge becomes available

Benha University HospitalDelta (Mansura) & Benha Fertility Centers

Email:elnashar1953@yahoo.com