Premature Ovarian Failure

Premature Ovarian Failure

What is premature ovarian failure?

 

 When a woman’s ovaries stop working before age 40, she is said to have premature ovarian insufficiency (POI) or premature ovarian failure (POF) also, known as premature menopause, is a common condition, affecting 1–2% of women younger than 40 years of age and 0.1% of women, younger than 30 years of age. When this happens, a woman’s menstrual cycles become irregular and stop. Her ovaries stop making hormones such as oestrogen and progesterone and she stops releasing eggs (ovulating) regularly or at all.

Some women develop POF when they are teenagers, even before they start to have menstrual periods. If that happens, the teen will never experience normal function of her ovaries. For other women experiencing POF, their ovaries may continue to intermittently release (ovulate) eggs and make hormones; these women may continue to have menstrual cycles for months or years before their ovaries completely shut down. For this reason, the currently used term POI is preferred to the older terminology “premature ovarian failure (POF).

 Causes of Premature Menopause 

In human females, the process of ovarian follicular maturation, or maturation of eggs, is a highly organised and complex process. Maturation of Eggs is the progressive maturation of small primordial follicles that progress to become large ovulatory follicles. When follicles eventually mature, the oocytes (eggs) are released from the surface of the ovary. They are collected by the uterine tube, and  proceed to become fertilised.

The causes of POF remains unknown in most cases. A genetic cause of POF is identified in few patients, i.e. in 5-7% of the total cases, whereas causes remains most often undiscovered. Fragile X syndrome is one of the genetic causes of POF which can be transmitted in the family.

Women receiving cyclophosphamide for either kidney diseases or rheumatoid arthritis are at risk of developing POF.

Malnutrition and cigarette smoking are perhaps the only consistent environmental features associated with an earlier menopause.

The first known significant cause is damage to the ovaries, such as that caused by iatrogenic agents like chemotherapy or radiotherapy or pelvic surgery may be

associated with ovarian failure. Surgical menopause may be induced by removal of ovaries, but interestingly hysterectomy to remove the uterus is also associated with an earlier menopause.

Premature ovarian failure (POF) may be considered as an autoimmune endocrine disease. Autoantibodies and lymphocyte subset changes are associated with premature ovarian failure. This problem can run in family as well.

 

What POF women experience?

Women with POF experience menopausal symptoms,

such as hot flushes, night sweats and vaginal dryness, In addition, there is increased risk of developing osteoporosis because of the lengthened time of exposure to reduced oestrogen similar to those going through a natural menopause.

For most women, it can be an unexpected and distressing diagnosis, with unpleasant symptoms, but made worse by the fact that it coincides with infertility.

Premature ovarian failure (POF) is a disorder associated with female infertility, and it affects approximately 1% of women under the age of 40 yr . It can be attributed to two major mechanisms: follicle dysfunction and follicle depletion .

Despite having amenorrhea and markedly elevated serum gonadotropin levels, some women with karyotypically normal can go to spontaneous premature ovarian failure. Nevertheless, they have ovarian follicles that function intermittently. Graafian follicles capable of responding to these high FSH levels are faced with high serum LH levels as well, which might prevent normal follicle function.

Premenopausal women may be at risk for the development of osteoporosis. However, bone loss in women with amenorrhea from other causes has not been assessed. Women with POF have diminished general and sexual well-being and are less satisfied with their sexual lives than other women

TREATMENT

 

Many women with POF would benefit from symptom relief by the use of exogenous steroids, to compensate for the loss of ovarian hormone estrogen and possibly progesterone and androgens. Menopausal symptoms, such as hot flushes, night sweats and vaginal dryness can be relieved by oestrogen replacement, such as sequential HRT or oral contraceptive pill.

Infertility In POF

Infertility is a significant issue for most women undergoing POF. A number of treatment regimens have been evaluated with the aim of restoring fertility. However, treatments with clomiphene, Gonadotrophins, GNRH agonists or immunosuppressants do not significantly improve the chance of conception and are not used.

The only reliable fertility treatment is the use of donor eggs. It is an assisted reproductive procedure that is widely practised in most countries. At present, in vitro maturation of immature follicles is possible. But in vitro growth and maturation from stored ovarian tissue is not reliably achievable in humans. For women with impending POF, there may not be any alternatives. Young women about to begin cancer treatment are encouraged to attempt a cycle of IVF if time permits. They can go for storing  embryo or eggs  for later use.

In addition, young women may store ovarian tissue, in the hope that at a later stage their tissue can be reimplanted, or that the use of in vitro growth and maturation of immature follicles may restore fertility

Women suffering from oestrogen deficiency should be recommended a number of measures to protect against osteoporosis. It includes increased physical exercise, eating a diet rich in calcium and vitamin D and avoiding risk factors such as smoking and high alcohol intake.

Women with POF are advised to undergo HRT until the normal age of menopause addition of testosterone to HRT to improve sexual function and wellbeing.

Premature ovarian failure (POF), a major life-changing condition that affects a significant proportion of young women. It remains an enigma and the researcher’s minefield. As women increasingly survive childhood cancers due to improved iatrogenic interventions, the number of POF sufferers will inevitably increase.

Patient Counselling

When primary ovarian insufficiency is diagnosed in the adolescent female, the patient and her family are often unprepared for such news with its implications for compromised fertility and the need for long-term hormonal therapy. Adolescents may demonstrate myriad emotions ranging from apathy or denial  and these emotions may be different from those of their parents or guardians. Parents can provide valuable insights about their daughters’ ability to appreciate the significance of the diagnosis to the treating practitioner and help in managing the situation.

How is ICSI treatment different from IVF?

How is ICSI treatment different from IVF?

What is intracytoplasmic sperm injection (ICSI)?

ICSI treatment is an option for conceiving with male infertility. It is an advanced fertility treatment which gives best success in the  hands of experts.

In human being formation of an embryo from a woman’s egg and a man’s sperm is a very complex phenomenon. The sperm of a man is a moving cell inside the body and it must reach to the egg at appropriate time to fertilize it as the released egg from ovary can survive for only 24 hours. At times this process doesn’t happen due to any of following problems in the man

  1. Sperm quantity may be too low – oligospermia
  2. Azoospermia- No sperms are found
  3. Defects in sperm movement – Asthenospermia
  4. Sperm cannot penetrate the egg due to a thick covering – thick zona

Before a man’s sperm can fertilize a woman’s egg, the head of the sperm must attach to the zona of the egg. Once attached, the sperm penetrates through the outer layer to the inside of the egg (cytoplasm), where fertilization takes place.

Sometimes the sperm cannot penetrate the outer layer, for a variety of reasons. The egg’s outer layer may be thick or hard to penetrate or the sperm may be unable to swim. In these cases, a procedure called intracytoplasmic sperm injection (ICSI) can be done to fertilize the egg inside the labaoratory. During ICSI, a single sperm is injected directly into the cytoplasm the egg.

 

How ICSI is different from IVF?

 

There are two ways that an egg may be fertilized in the laboratory: IVF and ICSI. In traditional IVF, 50,000 or more swimming sperm are placed next to the egg in a laboratory dish. Fertilization occurs spontaneously when one of the sperm enters into the cytoplasm of the egg. In the ICSI process, a tiny needle, called a micropipette, is used to inject a single sperm into the center of the egg. Fertilization achieved through ICSI can be up to 80-90% whereas through IVF it is aound 50 -60 %. With either traditional IVF or ICSI, once fertilization occurs, the fertilized egg (now called an embryo) grows in a laboratory for 2 to 5 days before it is transferred to the woman’s uterus (womb).

 

Why ICSI is needed?

 

ICSI helps to overcome fertility problems, such as:

  • The male partner produces too few sperm to do artificial insemination (intrauterine insemination [IUI]) or IVF.
  • The sperm may not move in a normal fashion, hence cannot reach up to the egg in time.
  • The sperm may have trouble attaching to the egg , Intra cytoplasmic sperm injection overcomes this.
  • Azoospermia due to a blockage in the male reproductive tract may keep sperm from getting out. In these couples the sperms are obtained directly from Testes through a minor procedure like PESA or TESE. ICSI helps these couples to achieve a pregnancy even though no sperms are found in semen analysis.
  • At times, traditional IVF fails to create embryos in some patients. ICSI can achieve fertilization in such patients regardless of the condition of the sperm.
  • ICSI is used along with IVM (In vitro maturation of eggs).
  • ICSI is necessary where frozen eggs are used for fertilization.

 

Does ICSI work for all?

 

ICSI fertilizes up to 80% of eggs. But certain issues may occur during or after the ICSI process:

  • Some or all of the eggs may be damaged. Hence it is advisable to take help of an expert embryology department.
  • The egg might not grow into an embryo even after it is injected with sperm. This can happen due to any inherent problem in any one of the couple.
  • The embryo may stop growing after fertilization due to several reasons.

 

Once fertilization takes place, a couple’s chance of achieving pregnancy is same for IVF and ICSI. Chances of Pregnancy in humans is up to 30-40 % even with very good embryos. This is due to the low implantation capacity of human uterus.

ICSI treatment

ICSI treatment

Can ICSI affect a baby’s development?

 

If a woman gets pregnant naturally, there is a 1.5% to 3% chance that the baby will have a major birth defect. The chance of birth defects associated with ICSI is similar to IVF, but slightly higher than in natural conception.

The slightly higher risk of birth defects may actually be due to the infertility and not the treatments used to overcome the infertility.

Certain conditions have been associated with the use of ICSI, such as Beckwith-Wiedemann syndrome, Angelman syndrome, hypospadias, or sex chromosome abnormalities. They are thought to occur in far less than 1% of children conceived using this technique.

 

Some of the problems that cause infertility may be genetic. For example, male children conceived with the use of ICSI may have the same infertility issues as their fathers. Couple should go through a counselling process at a standard ICSI center with the help of Infertility specialists and embryologists.

 

 

Infertility : When to see a doctor ?

Infertility : When to see a doctor ?

What should I Know before meeting a Fertility Specialist?

  • WOMEN – A woman’s fertility gradually declines with age, especially in her mid-30s, and it drops rapidly after age 37. Infertility in older women may be due to the number and quality of eggs, or to health problems that affect fertility.

When to see a doctor if you are a female patient?


You probably don’t need to see a doctor about infertility unless you have been trying regularly to conceive for at least one year. Talk with your doctor earlier, however, if you’re a woman and:

  • You’re age 35 to 40 and have been trying to conceive for six months or longer
  • You’re over age 40
  • You menstruate irregularly or not at all
  • Your periods are very painful
  • You’ve been diagnosed with endometriosis or pelvic inflammatory disease
  • You’ve had multiple miscarriages
  • You’ve undergone treatment for cancer

When to see a doctor if you are a male patient?


  • You have a low sperm count or other problems with sperm
  • You have a history of testicular, prostate or sexual problems
  • You’ve undergone treatment for cancer
  • You have testicles that are small in size or swelling in the scrotum known as a varicocele
  • You have others in your family with infertility problems

What are General factors responsible for infertility?


  • Diabetes mellitus,
  • thyroid disorders,
  • undiagnosed and untreated coeliac disease,
  • adrenal disease

What are environmental factors responsible for infertility?


Environmental factors

  • Glues,
  • Volatile organic solvents
  • Pesticides.
  • Tobacco smokers are 60% more likely to be infertile than non-smokers.

 What is the effect of age on fertility? 


  • Age.
    • WOMEN – A woman’s fertility gradually declines with age, especially in her mid-30s, and it drops rapidly after age 37. Infertility in older women may be due to the number and quality of eggs, or to health problems that affect fertility.
    • MEN -Men over age 40 may be less fertile than younger men .
  •  What is the effect of tobacco on fertility? 


    Smoking tobacco –

    • reduces the chances of pregnancy.
    • reduces the possible benefit of fertility treatment.
    • Miscarriages are more frequent in women who smoke.
    • Smoking can increase the risk of erectile dysfunction
    • low sperm count in men is common in tobacco use.

 What is the effect of tobacco on fertility? 


  • WOMEN -Avoid alcohol if you’re planning to become pregnant. Alcohol use increases the risk of birth defects, and may contribute to infertility.
  • MEN – Heavy alcohol use can decrease sperm count and motility.

 What is the effect of Weight on fertility? 


  • Overweight- Inactive lifestyle and being overweight may increase the risk of infertility.
    • WOMEN -Ovulation Disorders .
    • MEN – A man’s sperm count may also be affected if he is overweight so a normal weight is always healthy for fertility.
  • Underweight. Women at risk of fertility who follow a very low calorie or restrictive diet.So eat healthy foods and develop healthy habits .

What is the effect of Exercise on fertility? 


  • Exercise- Insufficient exercise contributes to obesity, which increases the risk of infertility.
  • Heavy Exercise – Ovulation problems are associated with frequent strenuous  and  intense exercise in women who are not overweight.Hence , it is important to avoid heavy exercise when you want to be pregnant.

What are infections associated with infertility?


  • Sexually transmitted infections 
  • chlamydia,
  • gonorrhea
  • Adeno-associated virus might have a role in male infertility so it is important to have a screening for these infections.


  • WOMEN – A woman’s fertility gradually declines with age, especially in her mid-30s, and it drops rapidly after age 37. 
  • MEN -Men over age 40 may be less fertile than younger men .


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Gender Assignment at birth, A Challenge For Parents

Gender Assignment at birth, A Challenge For Parents

Biggest Assignment as a Parent- Raising a child with Genital Ambiguity

The decision to have a baby is the first step in a lifelong commitment of love, time, and financial resources and dealing with a baby with sexual ambiguity is devastating and painful .

Sexual ambiguity is a complex issue. An accurate diagnosis is essential and may take some time. Sex of assignment must be based not only on the underlying diagnosis and karyotype but also on the potential for adult sexual function, fertility, and psychological health. For these reasons, input from several specialties, including endocrinology, genetics, neonatology, psychology, urology, and an ethicist, is important. All members of the team must communicate adequately with each other. Parents must fully understand the medical recommendation for sex assignment and required therapy. They must wholeheartedly agree and support the assigned sex to avoid ambivalence, which can lead to gender confusion and psychological trauma for the child.

Parents may be dealing with two major categories of children presenting with this problem:

  • Virilized 46, XX females –females look like male
  • Under virilized 46, XY males- males look like female

The most common cause of sexual ambiguity in newborns is congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency. Adrenal gland is situated above the kidneys and secretes several hormones.

As a general rule, gonadal tissue containing Y chromosomal material is at higher risk for development of malignancy.

When infant is born with ambiguous genitalia, and the sex of the infant is uncertain, what next ?

Accept the truth, cooperate with medical professionals as further testing is necessary to determine the infant’s sex. Explain all the relevant history during pregnancy that may help in a diagnosis.

 

Reference to more commonly understood birth defects may be useful. Several days may be necessary to complete the testing and a team will participate to make an accurate diagnosis and a considered recommendation.

 

Completion of the birth certificate should not be postponed, and sex assignment should not be delayed. Accept the sex assigned by Medical team.

What can cause genital ambiguity in newborn? Is it preventable?

Drug ingestion, alcohol intake, and ingestion of hormones during pregnancy can lead to such a situation. Hence Maternal history is particularly important. Progestational (androgenic) therapy used for threatened abortion or androgens for endometriosis during pregnancy should be avoided as far as possible. If the mother has signs of excessive androgen or parental family history for occurrence of ambiguity, neonatal deaths, consanguinity, or infertility it can lead to sex disorders.

 

What is the extent of problem?

The most common cause of a virilised female is congenital adrenal hyperplasia (CAH). Virilisation may also be caused by maternal ingestion of androgens or synthetic progesterone during the first trimester of pregnancy. The measurement increased ACTH in blood is useful for making a diagnosis. These babies have female chromosomes with male outlook, however they do have ovaries and uterus like any other female child.

 

An undervirilized male (previously called male pseudo hermaphroditism) refers to a male with female external genitalia. The abnormality may range from various grades of feminisation to a completely female phenotype. Such disorders result from deficient androgen stimulation of genital development and most often are secondary to testosterone biosynthetic defects. These boys have male chromosomes with female outward looks.

How the condition is diagnosed? What are the tests done?

The diagnosis of the origin of sexual ambiguity can rarely be made by examination alone, it is always combined with a series of tests. Tests are directed to determining the presence or absence of palpable gonads (presumably testes), the presence or absence of a uterus, and the karyotype to allows classification of the infant as a virilized female, an under virilized male, having a disorder of gonadal differentiation, or having one of the

unclassified forms. Certain forms of CAH may cause dehydration, hypertension, or areolar or genital hyperpigmentation. Turner’s stigmata may be present, including webbed neck, low hairline, and edema of hands and feet.

Radiographic studies are necessary to find out structural abnormalities like the presence of gonads and other reproductive structures. Pelvic ultrasound examination by qualified and experienced personnel should be performed as soon as

possible to look for a uterus. The presence of gonads, fallopian tubes, and a vaginal vault may also be determined. If necessary, a genitogram may be performed to see the lower reproductive organs like presence of vagina and its extent.

Because 21-hydroxylase deficiency is a common cause of sexual ambiguity, the level of 17-hydroxyprogesterone (17-OHP) should be assessed in all such infants who do not have palpable gonads. Screening of newborns for CAH with measurement of a 17-OHP level is now mandated in all 50 of the United States and in many countries throughout the world. A karyotype is essential and must be obtained expeditiously. Buccal smears are absolutely contraindicated because they are inaccurate. In many laboratories, a karyotype can be completed within 48 to 72 hours.

Defects in testosterone synthesis can be diagnosed by low testosterone levels with defect in its synthesis pathway (from the level of enzymes block either in the adrenal or in testicular pathways).

What is the role of parents in upbringing?

The decision about sex assignment must be carefully made, taking into consideration each “level” of sex determination. Sex assignment also depends on fetal sex hormone exposure, the potential for adult sexual function, and psychological and cultural considerations. It is vital that parents completely understand and support the decision because ambivalence about sex of rearing may result in gender confusion and psychological trauma.

Virilized females are usually assigned a female sex. They have normal ovaries as well as uterus and vaginal structures and, with surgical correction and steroid replacement, can have normal sexual function and achieve fertility. However, severely virilized females should be assigned a male sex.

Undervirilized males are often infertile, and sex assignment has usually been based on

phallic size. Adult social and fulfilling sexual function should be the primary goals of gender assignment. If male sex assignment is contemplated, a trial of depot testosterone (25 mg every 3-4 weeks) for 1 to 3 months indicates whether phallic growth is possible.

In patients with gonadal dysgenesis and Y chromosomal material, gonadectomy is necessary, and fertility is not possible. Internal duct structure is also frequently deranged. Small phallic size usually leads to a female sex assignment.

True hermaphrodites who have a unilateral ovary and uterine structures may have spontaneous puberty and normal fertility and may be raised as females. External genital size and structure may allow male assignment, but more commonly, external genitalia are poorly virilized, and affected infants are assigned a female sex.

 What are the future prospective regarding marriage, child bearing etc.?

Parents must understand that having normal sexual performance does not correlate with reproductive ability. However, physicians always give preference to sexual ability than childbearing probability. Our aim in parenting is to give the child a sexual identity which may contradict the genetic makeup and at places may force us to sacrifice the gonads for future life.

We have much to learn about gender identity and must consider which decisions may be made later than previously thought (e.g., surgery). Some surgical interventions are cosmetic, and some affected patients have expressed the wish to make the decisions in adolescence or adulthood. This field challenges many of our perceptions of sex and gender and our role as physicians. Although the infant with genital ambiguity presents a medical and social emergency, decisions should be made carefully, cautiously, and with all necessary biochemical and anatomic information available. Most important, the multidisciplinary team approach must involve the parents in an open and honest

discussion of the options. In the end, it is the parents who come first in decision making on sex assignment.

A male child be with complete androgen insensitivity should be raised female. Complete androgen insensitivity usually does not have suspicion of ambiguity in the new born period or early childhood. Affected children grow as normal females until puberty. They feminize with normal breast development at puberty because high levels of testosterone are aromatized to oestrogen, but they have no pubic or axillary hair and no menses because they lack uterus and ovaries. Gender identity is usually female. Patients come to medical attention because of lack of menses in adolescent period.

The diagnosis is therefore frequently made when patients are in their middle to late teens. If diagnosed early the testes should be removed to prevent cancer and oestrogen therapy should start early. This therapy helps in developing the vagina and performance as a female is not compromised.

Undervirilized males traditionally, infants with 5-alpha-reductase deficiency were raised as females until puberty, then continued life as males, and, in some cases, achieved fertility. More recently, however, the condition has been recognized early in life, and affected males are now raised from infancy as boys.

Virilized females are usually assigned a female sex. They have normal ovaries as well as

Uterus and ovaries and, with surgical correction and steroid replacement, can have normal sexual function and achieve fertility.

However, severely virilised females should be assigned a male sex. They can perform sexual function as a male but cannot reproduce as they don’t  have male gonads.

Patients with Y-related chromosomal or genetic disorders that cause mal development of one or both testes are said to have gonadal dysgenesis. They present with ambiguous genitalia and may have inadequate virilisation, uterus and vagina may be present in such children. The Y-containing dysgenetic testes are at risk for developing cancer and must be removed better reared as females.

How to deal with infertility in such cases?

Fertility potentiality is decided by karyotyping, presence of gonads and presence of uterus and vagina. Accordingly, they can go for gamete donation programme or surrogacy. The decision has to be taken after discussion with the couple.

 

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