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
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.
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.
What is ovarian drilling and how does it work?
ovarian drilling – In women with PCOS ovulation doesn’t occur regularly and usually they have ovaries with a thick outer layer. The ovaries make more testosterone, the male type of hormone. High testosterone levels lead to irregular menstrual periods, acne, and extra body hair.
Ovarian drilling is done to break the thick outer surface and destroy some of the testosterone producing tissue made by the ovaries. This can help the ovaries release an egg each month and start regular monthly menstrual cycles. This may reduce symptoms of excess testosterone
How drilling of ovary is done?
A minimally invasive surgery called laparoscopy is used for ovarian drilling. A thin, lighted telescope (laparoscope) is put through a small surgical cut (incision) near the umbilicus. A tiny camera is used to see the ovaries. The surgeon inserts tools through other tiny incisions in the lower belly and makes very small holes in the ovaries. This helps to lower the amount of testosterone made by the ovaries.
What are the benefits of drilling ovary?
About 50% of women get pregnant in the first year after surgery. Some women still may not have regular cycles after the surgery. Others may have other fertility problems (such as blocked tubes or a low sperm count) that can prevent pregnancy. Some women after a short period of regular ovulation may go back to previous irregular cycles.
For some women with PCOS, ovarian drilling will not fix the problems with irregular periods and ovulation, even temporarily. However, ovarian drilling can help a woman respond better to fertility medicines.
What are the risks of drilling ovary ?
There are certain risks of the surgery done for ovarian drilling .
Some of the risks are related to surgery. As with all surgical procedures, there are risks of bleeding, anaesthesia, and infection. Also, laparoscopy can cause injury to the bowel, bladder, and blood vessels. Very rarely, there is a risk of death.
There are also risks to fertility. If there is too much damage to the ovary during the ovarian drilling procedure, a woman may enter menopause at a younger age than expected. After the procedure, adhesions (scarring) can form between the ovaries and the fallopian tubes, making it hard to get pregnant. Most important in many women the beneficial effects are for too short period and they immediately go back to the previous status.
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
- Sperm quantity may be too low – oligospermia
- Azoospermia- No sperms are found
- Defects in sperm movement – Asthenospermia
- 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.
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.
Are you suffering from severe endometriosis?
What is Endometriosis?
Endometriosis is a common disorder of women of reproductive age. The most frequent clinical presentation of endometriosis is painful menstruation.
What are the common symptoms of endometriosis?
Endometriosis commonly present with painful menstruation, pelvic pain, pain during intercourse, infertility, and pelvic mass.
How to know the severity of endometriosis?
The correlation between the symptoms of endometriosis and the severity of disease is poor. Currently available laboratory markers are of limited value. At present, the best marker, serum CA-125, is usually elevated only in advanced stages and therefore not suitable for routine screening. Severity of endometriosis is difficult to determine from its symptoms. Usually symptoms are expressed according to area of involvement not depth of disease.
Who are affected by endometriosis?
Endometriosis usually starts in the ovary, it also can happen in the abdomen cavity affecting fallopian tubes, uterus and other pelvic organs like bladder and bowel. It affects women of reproductive age. Usually starts at around the age of 15 to 20 years and slowly spreads destroying nearby organs. It can subside spontaneously at menopause.
What is the correlation of CA 125 to endometriosis?
Plasma concentrations of CA-125 are increased in women with cystic ovarian and deep endometriosis and plasma concentrations are higher during menses than during the follicular and luteal phases of the cycle.
How ultrasonography and MRI are useful in Endometriosis?
Transvaginal ultrasound and magnetic resonance imaging are often helpful, particularly in detection of endometriotic cysts. Recently, trans rectal ultrasound and magnetic resonance imaging were shown to be valuable in detection of deep infiltrating lesions, especially affecting the rectum.
What is the role of Laparoscopy in endometriosis?
Direct assessment of endometriotic foci at laparoscopy may be viewed as a “gold standard” for identifying endometriosis. Laparoscopic removal of endometriosis significantly reduces pain and improves quality of life. Early diagnosis, surgical confirmation and therapy of endometriosis by laparoscopic techniques is recommended as soon as symptoms occur, even in adolescent girls.
Can a clinical test detect deep endometriosis?
A clinical examination during menstruation is proposed as a simple and reliable test to diagnose deep endometriosis. It also helps to decide which women may require bowel surgery. In >60% of cases deep lesions are “unexpected” findings at laparoscopy, these women are the candidates for bowel preparation before laparoscopy.
What is needed for definite diagnosis of endometriosis?
Diagnosis of endometriosis requires a careful clinical examination in combination with judicious use and critical interpretation of laboratory tests, imaging techniques, and, in most instances, surgical evaluation combined with biopsy results of excised lesions.
Which group of patients present with less severe symptoms?
Endometriosis, characterised by the ectopic localisation Of the endometrium, can be present as superficial implants, deep peritoneal lesions, and ovarian endometriomas, with or without associated pelvic adhesions. The frequency of dysmenorrhea and the frequency and severity of dyspareunia is less in patients with endometriosis located only on the ovaries than in patients with lesions at other sites.
What is Cystic Ovarian Endometriosis?
In some women, more severe forms present as either cystic ovarian or deep infiltrating endometriosis. Cystic ovarian endometriosis always has been recognized as a severe form because of its association with pelvic adhesions, infertility, and pelvic pain. Clinical examination during menstruation can diagnose reliably deep endometriosis, cystic ovarian endometriosis, or cul-de-sac adhesions. This test, preferentially combined with a follicular phase CA-125 assay, should be used to decide whether a preparation for bowel surgery should be given.
How CA 125 helps in pre-treatment of endometriosis?
The presence of pelvic nodularity during menstruation or a CA125 concentration higher than 35 U/mL can be used to decide in which women bowel pre-treatment should be given with a sensitivity of 87%, whereas <13%, will get an unnecessary bowel pre-treatment.
How deep endometriosis is treated?
Deep pelvic endometriosis may lead to severe pain, the treatment of which may require complete surgical resection of lesions. Infiltration of bowel is a difficult therapeutic problem. Preoperative diagnosis is difficult and digestive infiltration may remain unknown before surgery. This may cause damage to the gut with incomplete resection during surgery and sometimes may require repeated surgery. Both magnetic resonance imaging (MRI) and endoscopic ultrasonography are able to detect rectal infiltration but their usefulness in the preoperative staging is still not evaluated.
Can Endometriosis affect fertility?
Endometriosis is a chronic, progressive disease and may lead to severe destructions of reproductive organs and infertility in advanced stages.
Approximately 30% to 50% of women that have the diagnosis of endometriosis also struggle with infertility. Twenty five percent to 50% of women diagnosed with infertility also have endometriosis, but the endometriosis may not be severe enough to be the primary cause of infertility. White women have been reported to be more likely than African American women to have endometriosis. In addition, risk factors for endometriosis include below average body mass index, smoking, and alcohol use.
How ovulation is affected by endometriosis?
After ovulation, peritoneal fluid contains concentrations of progesterone and of 17 beta-estradiol that are 5 to 20 times higher than plasma concentrations in women with ovulatory cycles but not in women with unruptured luteinized follicles. Since viable endometrial cells were found in the peritoneal fluid of over 50% of women, both with and without endometriosis, a new hypothesis is presented about the cause of pelvic endometriosis and the association of pelvic endometriosis and infertility: pelvic endometriosis could be the consequence of infertility caused by the unruptured luteinized follicle.
What happens in Silent endometriosis?
Many times, a woman who has difficulty conceiving will have a case of endometriosis that does not come with severe symptoms. This is known as silent endometriosis. These silent sufferers eagerly crowd into the waiting rooms of in vitro fertilisation (IVF) clinics and reproductive specialists with the hope of conceiving. However, these women may have endometriosis, and the in vitro attempts they take may fail.
How endometriosis can lead to infertility in a woman and how it is treated?
Infertility due to endometriosis could be due to several abnormalities like tubal dysfunction, impaired ovarian reserve, worsening egg quality, defect in implantation and decreased sperm motility inside the female reproductive system. Infertility due to endometriosis at the earlier stages can be treated by simpler treatment like ovulation induction and IUI. However, at advanced stages it requires IVF / ICSI as the disease spreads rapidly and destroys the ovaries. At later stages, usually the women are completely depleted of their eggs and have to go through egg donation programme.
What are the precautions for women trying to conceive with endometriosis?
If you are experiencing severe pain during cycles it may be due to endometriosis, you must consult local gynaecologist. Diagnosis of endometriosis is usually done with pelvic ultrasound which may show chocolate cysts in the ovaries. It is always better to undergo a laparoscopy to check patency of tubes at this stage . If you are trying to conceive then it is a better option. If you are diagnosed as mild to moderate case of endometriosis you should regularly follow up with AMH levels. This can indicate extent of destruction of ovaries. Severe endometriosis needs immediate attention for fertility preservation, you may need IVF at this stage for optimum results.
Polycystic Ovary Syndrome (PCOS)
Which is the most common hormone disorder found in women?
PCOS is extremely prevalent and probably constitutes the most frequently encountered endocrine (hormone) disorder in women of reproductive age. Having the disorder may significantly impact the quality of life of women during the reproductive years, and it contributes to morbidity and mortality by the time of menopause.
What are the disorders associated with PCOS?
Polycystic ovary syndrome women are at increased risk for coronary heart disease and type 2 diabetes mellitus. Their risk factors include central obesity, hypertriglyceridemia, low levels of high-density lipoprotein (HDL) cholesterol, hypertension, and elevated fasting plasma glucose concentrations. Polycystic ovary syndrome women should undergo screening for hypertension, abnormal lipid profiles, insulin resistance, and reproductive disorders including cancer of endometrium.
What is PAO?
A subgroup of women (up to 30%) may have subtle abnormalities resembling Polycystic ovary syndrome called PAO. While PCOS occurs in at least 5% of the population, the isolated finding of polycystic-appearing ovaries (PAO), which meets the classic ultra-sonographic criteria, occurs in 16–25% of the normal population without evidence of the full-blown syndrome. These characteristics include androgenic ovarian responses to stimulation with gonadotropins, as well as metabolic changes such as lowered high density lipoprotein-C levels and evidence of insulin resistance. While these data generated by our group need further assessment, these findings suggest that important yet silent abnormalities may exist in otherwise normal women who have a trait of Polycystic ovary syndrome (namely PAO).
What is the most important reproductive concern in women with PCOS?
The most frustrating reproductive concern for women with PCOS is pregnancy loss. The spontaneous abortion rate in Polycystic ovary syndrome is approximately one third of all pregnancies. This is at least double the rate for recognized early abortions in normal women (12–15%). Reasons for this are unclear although hypotheses include elevated LH levels, deficient progesterone secretion, abnormal embryos from atretic oocytes, and an abnormal endometrium.
How PCOS negatively impact psychosocial development of young women?
Women with PCOS, particularly those with hirsutism, have an increased prevalence of reactive depression and minor psychological abnormalities. There is also evidence of increased psychological stress and an increased catecholamine response to provoked stress. The overall quality of life is decreased in hirsute women. The presence of hirsutism and menstrual irregularities, especially in younger patients, is extremely distressing and has a significant negative impact on their psychosocial development.
Which cancer has increased risk in women with PCOS?
Women with Polycystic ovary syndrome are at increased risk of endometrial cancer. Chronic unopposed estrogen exposure is probably the proximate risk factor. This may be confounded by obesity, hypertension, and diabetes, which are known correlates of endometrial cancer risk. It is imperative to screen all women with Polycystic ovary syndrome, even those who are considered too young to develop endometrial hyperplasia and carcinoma.
Can low grade inflammation be a risk factor of PCOS?
Women with Polycystic ovary syndrome have significantly increased CRP concentrations relative to those in healthy women with normal menstrual rhythm and normal androgens. Inflammatory marker like CRP concentrations is more with PCOS. It correlates with the degree of obesity and inversely with insulin sensitivity, although not with total testosterone concentrations.
Which is a better predictor of metabolic syndrome in PCOS?
Obesity, a key determinant of insulin concentrations, appeared to have an independent effect on risk for the metabolic syndrome. In Anovulatory Polycystic ovary syndrome women a waist circumference of >83.5 cm along with biochemical evidence of hyperandrogenism is a powerful predictor of the presence of metabolic syndrome and insulin resistance. Age and central obesity (waist-hip ratio/waist circumference) are better predictors of metabolic syndrome in women with Polycystic ovary syndrome compared to other parameters including BMI.
How Metformin helps in PCOS?
Metformin is the most thoroughly investigated insulin-lowering agent used to treat PCOS; it enhances insulin sensitivity in the liver, where it inhibits hepatic glucose production, and in muscle, where it improves glucose uptake and use.
The persistence of regular ovulatory menstrual cycles in the 6 months after the end of treatment demonstrates that metformin treatment provides lasting benefits. All girls maintain a BMI <25 kg/m2, and this can play a role in normal ovulation menstrual cycles.
What is the role of AMH in diagnosis of Polycystic ovary syndrome ?
Serum anti-Mullerian hormone (AMH), produced in the ovaries by small follicles, is usually elevated in women with PCOS and correlates with the severity of this syndrome. AMH plays an important role in inhibiting follicular development by decreasing the sensitivity of the follicles to FSH and by inhibiting granulosa cell aromatase. Serum AMH appears as a sensitive and specific parameter that predict Polycystic ovary syndrome than antral follicle count and ovarian volume.
What is the source of DHEA in Polycystic ovary syndrome ?
Serum DHEAS has been found to be elevated in some women with polycystic ovary syndrome . In Polycystic ovary syndrome , it has been found that there are actually two different sources of androgens, the ovary and the adrenal. In women with PCOS, the theca cells are overactive and proliferate excessively, producing too much testosterone. Unfortunately, in 40-50% of women with PCOS, there is also another source of androgens, which is the adrenal glands. The adrenal glands produce all of the DHEA in the body.
What causes PCOS in non-obese women?
All women with PCOS are not obese. Between 20–50% of women with PCOS are normal weight or thin, and the pathophysiology of the disorder in these women may differ from that in obese women. It has been suggested that PCOS develops in non-obese women because of a hypothalamic-pituitary defect that results in increased release of LH, and that insulin plays no role in the disorder.
These women tend to have an increased waist to hip ratio and are insulin resistant and hyperinsulinemic compared to their normal counterparts.
How the lean PCOS are treated?
Even normal weight and thin women with PCOS respond to pharmacological measures to improve insulin sensitivity, such as administration of agents like metformin, with decreases in ovarian androgen production and serum androgens. Administration of myoinositol (3 g per day) reduce luteinizing hormone (LH), high-sensitivity C-reactive protein (hs-CRP) (inflammation), and androgens, as well as improve insulin tolerance test, in lean patients with PCOS.
How infertility in PCOS treated?
Lifestyle modification is very important in the treatment for PCOS, because weight loss and exercise have been shown to lead to improved fertility and the lowering of androgen levels. Ovarian stimulation along with insulin sensitizers help in many instances. IVF is an alternative option in Polycystic ovary syndrome . GnRH antagonist protocol appears to significantly reduce the rate of severe OHSS in these women. The average number of oocytes recovered is higher but rate of immature oocytes is more and fertilization rate is lower in the PCOS group.
Does IVM help in PCOS?
In-vitro maturation treatment can now be offered as a successful option to infertile women with polycystic ovaries or polycystic ovary syndrome. It is possible to combine natural cycle in-vitro fertilization with immature oocyte retrieval followed by in-vitro maturation, and thus offer women with various causes of infertility reasonable pregnancy and implantation rates without recourse to ovarian stimulation.
What is the effect of bariatric surgery in PCOS?
Bariatric surgery has been increasingly popular to treat morbid obesity associated with PCOS. In the larger population as the surgery has become safer with primarily a laparoscopic approach and selection of a healthier population for surgery, long-term survival is now superior with versus without the surgery.