Early Menopause and Premature Ovarian Failure

I will try to explain in this article some aspects of the “PREMATURE OVARIAN FAILURE” and

Dr. Filiberto Di Prospero

Dr. Di Prospero is considered an expert in early menopause and premature ovarian failure

“EARLY MENOPAUSE” , some of the most controversial topics of modern gynecology. I have also written some books (both in Italian and in English) on this subject that  you can find it in the resource area of ​​this site.

As you probably know the average age of menopause (cessation of menstruation and reproductive activity) is about 50 years with an oscillation considered normal between 48 and 52 years old. Unlike the menarche (age of onset of first menstruation), which has progressively anticipate their occurrence probably directly related to the improvement of socio-economic conditions and food, the age of onset of menopause over the years showed no variation.

However MENOPAUSE, showing a strong dependence on genetic and hereditary susceptibility to external factors such as: cigarette smoking; infectious, some pharmacological or radioactive therapies.

The ovaries, two in number and placed symmetrically in the pelvis laterally to the uterus

have a double function: reproductive and endocrine. While the reproductive function, linked to the presence of ovarian follicles certainly stop with menopause the endocrine activity contrary to what has always been considered not completely ends.

In fact, it is well established that although the dramatic drop in estrogen the ovaries continues to secrete a small amount of androgenic hormones very important for health status in post-menopause.

The ovarian follicle component is more sensitive to external agents and goes decreasing  with age. About 3.5 million oocytes are present in each ovary at the beginning of fetal life, only 1.000.000 at birth and only 300-400,000 for each ovary at menarche.

About five follicles at each menstrual cycle begin growth and only one of them, the dominant follicle, will arrive at ovulation emitting oocyte and allowing the conception. A good part of the follicles not are engaged in this growth and for reason not yet completely clarified ( immunological?) undergoes a process known as atresia.

follicle growth and ovulation

Follicle growth and ovulation. Note the antral follicle.

Follicular growth (characterized by the predominant estrogen secretion), ovulation and subsequent luteal phase (characterized by secretion of estrogen and progesterone) stimulate the inner part of the uterus (endometrium) resulting in a normally menstrual rhythm of 28 days with oscillations in the limit of 7 days.

The whole mechanism is regulated by two small pituitary hormone FSH (Follicle Stimualting Hormone) and LH (luteinising hormone). Of these, FSH is an excellent indicator of the ovarian health and its levels are inversely correlated (estrogen negative feedback) to follicular count; in fact FSH increases in all the conditions of ovarian insufficiency and especially after menopause.

Premature menopause or “Early Menopause” better known today as Premature Ovarian Failure (POF) is a condition characterized by ovarian functional exhaustion with secondary amenorrhea (absence of menstruation), infertility, and autonomic symptoms such as hot flashes, sweating and insomnia before 40aa of age.

POF it is a complex syndrome for a long time incorrectly identified simply as menopause. In fact disease physiopathology and onset mechanism, clinical and hormonal changes and the possibility of spontaneous remission are very different from natural menopause.

From the point of view of epidemiology Early Menopause affects about 1% of women under 40aa and a family aggregation is present approximately in 20-30% of patients. The problem is therefore very relevant considering also the female reproductive implications in a population that tends more and more to delay the age of first pregnancy

The “classic definition” of Premature Ovarian Failure or “early menopause” is split as we have seen the cessation of menstrual flow, the appearance of autonomic symptoms with hot flushes and sweating, infertility and hypoestrogenism (estrogen deficiency) before 40 years of age. In reality things are not always so and the symptoms can be associated and appear differently at different times and with varying intensity.

For example, not infrequent are the so called “hidden forms”, ie those situations where despite the presence of regular menses ovarian reserve and egg quality are reduced: otherwise unexplained infertility in which a determination FSH on the 2nd or 3rd day of the menstrual cycle shows values ​​higher than 10-12 IU / ml.

Even the symptom progression (from menstrual irregularities to secondary amenorrhea) does not follow e regular precise time, it is not uncommon to assist spontaneous remissions in situations only apparently irreversible.

The World Health Organization (WHO) has suggested a distinction between two main types of Ovarian Failure differentiating a primitive form due to a damage of the ovary and a secondary form in which the ovary is actually healthy but is not adequately stimulated by central causes Hypothalamic- pituitary.

The POF disease is undoubtedly a primitive forms and some risk factor are been identified:

  • familiarity (other cases of premature menopause in the family)
  • autoimmune diseases (in particular thyroiditis Haschimoto but also vitiligo and Syndromes Poliendocrine)
  • cigarette smoking
  • hysterectomy, tubal ligation, embolization treatment for fibromatosis (probably through a reduction in the blood supply)
  • laparoscopic intervention for ovarian endometriotic cysts (follicular depletion mechanism uncertain but likely to thermal damage)
  • repeated surgery on the ovaries, prolonged follicular growth inductions, exteiatrogenic menopause
  • congenital enzyme defects (galactosemia)
  • chromosomal abnormalities
  • viral infections (oophoritis)
  • Chromosomal abnormalities relate to deletions, translocations, supernumerary attendance generally the X chromosome (the best known example is Turner’s syndrome and Down 45XO 47XXX) but also autosomal dominant and recessive forms are not uncommon.

Among the genetic abnormalities special attention deserves the premutation of the FMR1 gene on the long arm of the X chromosome also called “Fragile X Syndrome” in these patients, in fact it often assite onset of premature ovarian failure.

The most common form of premature ovarian failure or early menopause is idiopathic; that is the primitive form of the ovary where usually it’s not identified an etiology. In these forms, however, has been strongly suggested an autoimmune mechanism against the ovary often associated with other autoimmune diseases.

With regard to the DIAGNOSIS next to the detection of the symptoms (sometimes completely absent) is very important the  FSH and Anti-Mullerian Hormone (AMH) assay.

FSH is usually the first test conducted to evaluate the ovarian reserve (reproductive potential).

menopause and ovarian reserve

Menopause usually occurs between the age 48 and 52. Note the FSH and ovarian reserve relationship.

In fact tends to increase with the decrease of the assets of follicular estrogen production. Its determination is usually done the morning of the 2nd or 3rd day of menstrual flow. Values ​​greater than 12 IU / L are considered alarming. However It should be consider that at least two FSH different evaluations are necessary.

Anti Mullerian Hormone (AMH) tends to decrease in ovarian faillure and currently is the most reliable hormonal investigation for the assessment of ovarian reserve; it can be dosed at any time of the cycle. The AMH is a glycoprotein secreted by granulosa cells of primary and secondary preantral follicles and small antral follicles (2-6mm).

The Inhibin B is produced by the follicles recruited and is now considered as a marker (expensive) to monitor follicular growth than a tool for the assessment of ovarian reserve.

An important diagnostic role has also the transvaginal ultrasound: it allows to evaluate gonadal volume and antral follicles (follicular structures with a diameter between 3 and 10 mm).

Follicles Antral Counts (AFC) has proved particularly useful in determining the reproductive

antral follicle count and age

Ovary ultrasound is very useful in antral follicle count and ovarian reserve evaluation. Note the decrease with age. Example: a) hight count b) low count.

potential (ovarian reserve) especially when considering those with a diameter between 3 and 6 mm. The count of the antral follicles is conducted in a very early period of the cycle, between the second and the third day with a probe endovaginal traditional or three-dimensional.

On the data available in the literature are reasonably considered reassuring a total ovarian volume >  6 cm3 and the presence of both ovaries at least 7 antral follicles.

The Dynamic Tests, i.e.  Clomiphene Citrate and exogenous FSH have lost much of their utility and are used exclusively in anticipation of Assisted Reproduction in patients with ovarian modest deficit (forms called preclinical or occult).

I would now to focus on two aspects that I consider of great importance: prevention and early detection.

The PREVENTION is certainly possible to avoid the risk factors that are already known. In addition, rescue strategies (pill, artificial menopause with GnRH analogues, storage of oocytes or ovarian tissue, laparoscopic ovarian displacement) can also be considered before embarking on cycles of radiation or chemotherapy potentially harmful to the gonads.

The choice of treatments (medical and / or surgical) conducted for any reason should always consider the impact of reproduction.

In addition, women with a family history of early menopause, smokers and / or suffering from autoimmune diseases should be aware of an increased risk for POF paying particular attention to any menstrual changes or difficulty in conception.

The EARLY DIAGNOSIS with the actual testing is certainly possible and reproductive strategies can be considered before advanced stages of the disease. Always think of a diminished ovarian reserve in front of otherwise unexplained infertility or infertility (hidden forms).

THERAPY is considered when the gonadal deficiency cause irregular or absence of menstruation, neuro-vegetative symptoms (insomnia, hot flashes, decreased performance …). The commonly used drugs contain estrogens and progestins (E / P) formulations that guarantee a good genital tropism and the maintenance of induced menses. Treatment options are very personalized and meet the safety criteria and appropriateness; once begun, with the appropriate controls, therapy should be continued until the age of natural menopause.

Treatment of Early Menopause involves the use of estrogens and progestins and especially in women with an intact uterus, the association with the progestin is mandatory and generally made according to called “sequential pattern”, the most similar to the physiological menstrual cycle.

Not uncommon is the choice of oral contraceptives that provide convenience and prevention of unwanted pregnancies (on HRT treatments have been described rare remissions with pregnancies).

The non-therapeutic intervention results in the onset of symptoms of estrogen deficiency as genital dystrophy, Osteopenia and Osteoporosis, accelerated aging, cardiovascular problems.

Combining different routes of administration is possible: i.e. to bind a systemic therapy with local vaginal therapy to treat vaginal and urogenital dystrophy.

The administration of androgens, testosterone (T) Dehydroepiandrosterone (DHEAS) is generally considered to be in the presence of surnalico deficit, severe changes in libido and mood, significant impairment of performance

To consider that a heightened genital dystrophy and reduced uterine volume also have implications on a possible attempt reproductive PMA (egg donation).

All patients with Ovarian Failure even if only hidden or poorly symptomatic must follow some RECOMMENDATIONS:

Consult your gynecologist regularly and also adhere to regular check-ups (which may include your cardiovascular system, skeletal and metabolic);
Avoid all factors can potentially worsen the ovarian function (eg cigarette smoke);
Do not confuse your illness with typical menopause onset after 48-50 years, as you have seen are very different conditions;
Pay attention to symptoms that may suggest a possible remission (discuss it with your gynecologist) and considered that even in apparently irreversible forms have been described pregnancies;
Followed scrupulously cancer screening programs but also monitor the function of other endocrine glands such as thyroid, pancreas, adrenal.
Spontaneous remission is a characteristic appearance of the primitive Shortcomings Ovary and unfortunately we do not have predictive tools in this regard. Remissions may alternate with periods of amenorrhea and worsening of symptoms leading to confusion for patients and sometimes even the doctors who do not know the disease.

Sometimes patients receiving hormone replacement therapy (HRT) experience a sudden breast tenderness, irregular bleeding or absence of flow from suspension, and in these cases it is wise to consult your gynecologist or the Hospital Centre of Reference for investigation.

While remissions are common experience of the pregnancies in these situations are really rare because the Ovarian Failure and Early Menopause not only result in a deficit of ovulation but also and mainly poor oocyte quality. It is precisely the poor oocyte quality which makes it difficult fertilization and exposes to early abortion and fetal malformations.

However I have had the pleasure to attend pregnancies decorse in a physiological manner and crowned by a comprehensive reproductive success but it is still very exceptional cases. Very important to consider in case of pregnancy in patients with POF collaboration with a gynecologist experienced in Reproductive Endocrinology. This not only for the initial therapeutic choices but also for the management of frequent associated endocrinopathies.

CONCLUSIONS Too many times I witnessed a late diagnosis of occult ovarian failure for many years and not appropriate attitudes against young women with premature menopause, a condition that if left untreated has serious clinical consequences. Then spread this disease aims to raise awareness of women and be able to do as much as possible prevention and early detection.

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Filiberto Di Prospero
Medical Doctor, Consultant in Gynecology and Obstetrics, Endocrinology and Metabolism. Director of Gynecologic Endocrinology Unit at Civitanova Marche General Hospital (Italy). Private clinics in Civitanova Marche, Rome and Milan.

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