Menopause

preceded by a period of duration of about 4 years during which the endocrine, biological and clinical features of changing ovarian function begin.
A common feature is the development of cycle irregularity in women with a previous history of regular menses.
This marks the onset of the menopausal transition (perimenopause).

Morphological changes in the ovary with ageing

ovarian follicle --> Graffian follicle
In each menstrual cycle: about 30 follicles are recruited --> only one becomes dominant follicle --> ovulation

Numbers of primordial follicles are maximal during fetal life and decline steadily with increasing age
acceleration in the rate of decline at about age 38 years, and by the time of the menopause few if any primordial follicles remain.
With the disappearance of follicles, the source of ovarian estrogens and inhibins is lost.
However, secretion of androgens (particularly testosterone) continues and is not significantly altered by the occurrence of the menopause.

The normal pituitary–ovarian axis

GnRH (hypothalamus) --> FSH, LH (pituitary)
an early follicular phase rise in FSH, a mid-cycle peak of both gonadotrophins, and relatively low levels of both during the luteal phase.
FSH --> E2
Follicular-phase FSH drives ovarian production of estradiol, increasing levels of which in the late follicular phase trigger the mid-cycle LH surge.
After ovulation, the granulosa cells of the dominant follicle are luteinized to form the corpus luteum, which is the source of progesterone.
Granulosa cells are also the source of the ovarian inhibins A and B.

Postmenopausal

↑↑↑ FSH
↑LH
↓ E2
↓ PG

reproductive ageing after 40 years is marked by a relatively rapid reduction in the number of primordial follicles and a consequent decrease in inhibin B secretion, with an increase in FSH that can maintain or increase estradiol and inhibin A secretion until follicular exhaustion occurs

Hormonal changes in the menopausal transition – FSH, E2, inhibins

FSH levels begin to increase further,
women whose menses occur at intervals of more than 3 months exhibit increased FSH, with a decrease in circulating estradiol and the inhibins

The postmenopausal phase 

The postmenopausal state (STRAW stages +1 and +2) elevated FSH and LH, low estradiol and progesterone, and well-preserved levels of testosterone. DHEAS decreases progressively.
The major circulating estrogen at this time is estrone.
Estrone levels are higher in obese women, who have more adipose tissue than lean women; this may explain why obese women are at greater risk of estrogen-related malignancies such as breast and endometrial cancer.

At the time of the final menses

FSH levels have reached about 50% of their final postmenopausal concentrations, which are 10–15-fold higher than those found in the follicular phase of reproductive-age women.
Estradiol levels are about 50% of those seen in the follicular phase during reproductive life, and continue to decline after the final menses to reach their nadir 2–3 years later. By this time, estradiol levels have decreased by 90% or more.

progesterone shows progressively fewer concentrations indicative of normal ovulation.
free androgen levels increase during the menopausal transition. It can therefore be said that the postmenopausal ovary is primarily an androgen-secreting organ,

the permanent cessation of menstruation that results from loss of ovarian follicular activity.
characterized by a continuation of vasomotor symptoms and by urogenital symptoms such as vaginal dryness and dyspareunia.
Premature menopause – before 40th year
Delayed menopause – cessation of menses after 54th year (less than 10% of females)

Factors that lower the age of physiologic menopause:
smoking, hysterectomy, Fragile X carrier, autoimmune disorders, living at high altitude,
history of certain chemotherapy medications and/or radiation treatment.

Physiology

as aging follicles become more resistant to gonadotropin stimulation, circulating FSH and luteinizing hormone (LH) levels increase.
lead to stromal stimulation of the ovary, with a resultant increase in estrone levels and a decrease in estradiol levels.
Inhibin levels also drop during this time because of the negative feedback of elevated FSH levels.
the most significant change in the hormonal profile is the dramatic decrease in circulating estrogen levels. Without a follicular source, the larger proportion of postmenopausal estrogen is derived from ovarian stromal and adrenal secretion of androstenedione, which is aromatized to estrone in the peripheral circulation.

Testosterone levels also decrease with menopause, but this decrease is not as marked as the decline in 17-estradiol.
Androgen-to-estrogen aromatization can occur in adipose tissue, muscle, liver, bone, bone marrow, fibroblasts, and hair roots

Clinical Effects of Menopause

hot flashes or flushes, insomnia,
weight gain and bloating, mood changes,
irregular menses, mastodynia, headache
symptoms may begin during perimenopause and continue for 5-10 years after menopause.

uterus becomes smaller. Fibroids, if present, become less symptomatic.
Endometriosis and adenomyosis are also alleviated
ovary diminishes in size and is no longer palpable during gynecologic examination.
Skin loses elasticity, bone mineral density (BMD) declines, and dense breast tissue is replaced by adipose tissue, making mammographic evaluation easier.

Osteoporosis

Bone densitometry is the most accurate clinical predictor of osteoporosis

Menopause Markers

Gonadotropin secretion increases: FSH, LH
Endometrial hyperplasia can be suggested by ultrasonography (an endometrial thickness of > 5 mm),

Replacement Therapy and Menopause

relief of vasomotor symptoms,
reduce the risk of unwanted pregnancy,
avoid the irregularity of menstrual cycles,
preserve bone.

Adverse effects of replacement therapy may include bloating, mastodynia, vaginal bleeding, and headaches.

Contraindications to estrogen therapy are undiagnosed vaginal bleeding, severe liver disease, pregnancy, venous thrombosis, and personal history of breast cancer.