Amber R. Cooper1 , Sharon N. Covington and Lawrence M. Nelson
(1)
Department of Obstetrics and Gynecology Division of Reproductive Endocrinology and Infertility, Washington University School of Medicine, St. Louis, MO, USA
Amber R. Cooper
Email: coopera@wustl.edu
Abstarct
A 29-year-old G0 woman presented to her gynecologist with the complaints of an inability to get pregnant and abnormal menses. She married 1 year ago and immediately stopped her oral contraceptives with hopes to conceive. She had irregular light cycles the first 3–4 months off of OCPs, 1 menses 3 months later, and none since that time (about 4–5 months). Her past medical history was unremarkable and her review of systems was noncontributory except for a 10 lb weight loss in the last 6 months, which she attributes to stress from an inability to conceive and vaginal dryness. She is on no other medications but does smoke 5–10 cigarettes/day, although is trying to quit. She had normal puberty and menarche at age 13 years. Her cycles had previously been regular and she had been on oral contraceptives for 8 years. Her family history was remarkable for a mother with rheumatoid arthritis and hypothyroidism, a father with type I diabetes mellitus, and a cousin with mental retardation. Her height is 61 in., weight 116 lb, and BMI 21.9 kg/m2. Physical and pelvic examinations were normal. Pregnancy test was negative. She was given a progestin challenge test and bled in response to it. Initial prolactin and thyroid studies were normal and basal follicle stimulating hormone (FSH) during her withdrawal bleed was 46 mIU/mL.
A Clinical Vignette
A 29-year-old G0 woman presented to her gynecologist with the complaints of an inability to get pregnant and abnormal menses. She married 1 year ago and immediately stopped her oral contraceptives with hopes to conceive. She had irregular light cycles the first 3–4 months off of OCPs, 1 menses 3 months later, and none since that time (about 4–5 months). Her past medical history was unremarkable and her review of systems was noncontributory except for a 10 lb weight loss in the last 6 months, which she attributes to stress from an inability to conceive and vaginal dryness. She is on no other medications but does smoke 5–10 cigarettes/day, although is trying to quit. She had normal puberty and menarche at age 13 years. Her cycles had previously been regular and she had been on oral contraceptives for 8 years. Her family history was remarkable for a mother with rheumatoid arthritis and hypothyroidism, a father with type I diabetes mellitus, and a cousin with mental retardation. Her height is 61 in., weight 116 lb, and BMI 21.9 kg/m2. Physical and pelvic examinations were normal. Pregnancy test was negative. She was given a progestin challenge test and bled in response to it. Initial prolactin and thyroid studies were normal and basal follicle stimulating hormone (FSH) during her withdrawal bleed was 46 mIU/mL.
Introduction
The ovary is one of the most enigmatic organs in the body. It peaks in oocyte quantity even before a female fetus is born, at approximately 20 weeks in utero, with 5–6 million oocytes. Yet even prior to this peak in oocyte number, the majority of oocytes begin to undergo apoptosis. By birth, 80–90% of oocytes are already lost [1]. Most consider the period of infancy through puberty a relatively quiescent time for the ovary, although during this time follicles are growing and oocytes are actively synthesizing mRNA and protein. By the time of puberty, there are less than 500,000 oocytes remaining and most likely 500 or less will ever grow to an optimal size for ovulation. From puberty to the time of menopause (which normally occurs at 51–52 years of age on average), there is a progressive decline in oocyte quantity and, most likely, quality. The last 10–15 years of menstruation are marked by an accelerated rate of oocyte loss, likely when the follicular pool reaches a critical threshold number of oocytes (thought to be around 25,000) [2]. As the follicle pool diminishes, less estradiol and possibly inhibin-B are released, leading to an increase in FSH. More rapid follicular development occurs and menstrual cycle length shortens partially due to early and more rapid recruitment. It may be that the individual age of menopause is related to the size of the established primordial follicle oocyte pool in utero, and, thus, when the functional pool is depleted, menopause will occur. It is also possible that the rate of expenditure of primordial follicles is accelerated above normal in some women. Natural menopause is an irreversible decline in reproductive function driven by primordial follicle quantity (Fig. 5.1) [1].
Fig. 5.1
Oocyte quantity (in millions) over the lifespan of a normal female, from in utero through menopause [1]
We prefer the designation of “primary ovarian insufficiency” (POI) as a more scientifically accurate term for what many still refer to as “premature ovarian failure” (POF) or “premature menopause.” The terms POF and premature menopause inappropriately suggest a state of complete, irreversible cessation of ovarian function. Fuller Albright originally coined the term POI in the early 1940s to report what is now evident to be a continuum of impaired ovarian function ranging from a mild dysfunction to severe abnormality [3]. Also, a majority of women interpret the term “failure” as stigmatizing and prefer the term POI as a more positive and more accurate description of their condition (unpublished data). Many prefer the term insufficiency because it conveys the message that there still remains some hope of pregnancy, albeit small. Published evidence has demonstrated that patients who feel more stigma related to this condition experience more symptoms of anxiety and depression, so there is good reason to use a term that is both more scientifically accurate and less stigmatizing to patients [4]. A diagnosis of POI comes with significant medical, genetic/heritable, psychologic, and reproductive health concerns. This chapter will describe the condition and provide data to aid the clinician in providing optimal care for women diagnosed with POI. It is our belief that women with POI are best served with a multidisciplinary health care treatment approach in order to address all of their health issues, preventative care, and counseling needs. These issues will be addressed in detail.
POI is defined as absent or irregular periods for 4 months or greater combined with menopausal range FSH in a woman under 40 years of age (Table 5.1). Most have previously defined it as a triad of amenorrhea, hypergonadotropism, and hypogonadism in women younger than 40 years of age. Yet for reasons often unknown to clinicians, 1–2% or more of women develop signs and symptoms of menopause prior to the age of 40 years, an age 2–3 standard deviations outside the normal range [1, 5]. The precise prevalence is difficult to determine, increases with age, and is dependent on the population studied. It may seem natural to call such a process “early menopause” or POF, which implies complete cessation of function of the ovaries and sterility at a significantly earlier age than normal, but these terms are not accurate for young women with this condition as mentioned above. It is well documented that these women have varying and unpredictable menstrual cycles, often periodically ovulate, and still spontaneously conceive 5–10% of the time [6–10].
Table 5.1
POI diagnostic criteria
• < 40 years of age |
• Absence or irregularity of menstrual cycles ≥4 months |
• Menopausal range FSHa (defined by individual laboratory criteria) |
aMenopausal range FSH values need to be repeated and confirmed on two occasions at least 1 month apart
Menopausal range gonadotropins may not correlate with the degree of ovarian function as they do in a naturally menopausal woman in her sixth decade of life or later. In fact, young women with POF may still ovulate and menstruate while on no therapy despite significantly elevated FSH values (Fig. 5.2) [10, 11]. Furthermore, ultrasound evaluation of these women frequently reveals continued follicular development unlike that in the naturally menopausal woman in her 50s who may have smaller ovaries with little to no basal antral follicles [9, 12]. Such follicular presence or development does not imply normal functionality in these patients. In most cases, the etiology remains a mystery even after thorough evaluation.
Fig. 5.2
Serial blood samples in an 18-year-old 46,XX patient with spontaneous POI diagnosed at age 14 years. Column a represents repeated FSH, LH, estradiol (E2), and progesterone (P4) measurements during 4 months of treatment with a GnRH agonist. Column Bdemonstrates continued ovulatory cycles and menstrual bleeds (red arrows or solid bars on the x-axis) despite significantly elevated FSH during 4 months of treatment with placebo injections [10, 11]
The Clinical Spectrum of POI
The presentation and symptoms experienced by women with POI vary depending on the etiology of the condition. Amenorrhea can be a manifestation of numerous underlying medical illnesses. Women who present with primary amenorrhea are less likely to have developed breasts to Tanner stage 5, less likely to have symptoms of estrogen deficiency, and more likely to have karyotypic abnormalities (50% or more), resulting in conditions such as Turner’s syndrome (45,X) [8]. Most adult women who are found to have hypergonadotropic hypogonadism are ultimately given a diagnosis of spontaneous 46,XX POI. Most of these women present with secondary amenorrhea, but many will initially report oligomenorrhea, polymenorrhea, menometrorrhagia, or other dysfunctional uterine bleeding. In women with secondary amenorrhea, estrogen withdrawal symptoms are common and infertility is sometimes part of the history, although for many women the condition precedes any attempt at conception.
Some women who will ultimately meet the criteria for a diagnosis of POI will be completely asymptomatic. Others may only present to subspecialists due to infertility or irregular menstrual cycles. Often while taking a detailed patient history, some clues may surface leading a physician to suspect POI, but this is not always the case. Regardless, it is often a random, or more commonly a basal (drawn on day 2–4 of the menstrual cycle), FSH value abnormality that directs the physician toward uncovering the earliest stage of POI, occult POI.
One way to differentiate between degrees of ovarian insufficiency is to categorize the clinical and laboratory findings, more specifically, to quantify their ovarian function based on their menstrual regularity, fertility, and FSH values. Using this sub-categorization of findings, clinicians can develop a spectrum, referring to women as normal, or as being in the occult, biochemical, or overt stages in the continuum of ovarian function associated with POI (Table 5.2) [6, 13].
Table 5.2
Clinical states of POI [6, 13]
Clinical State |
Serum FSH Level |
Fertility |
Menses |
Normal |
Normal |
Normal |
Regular |
Occult |
Normal |
Reduced |
Regular |
Biochemical |
Elevated |
Reduced |
Regular |
Overt |
Elevated |
Reduced |
Irregular or absent |
With the advent and rapid progression of assisted reproductive technologies (ART) in the last several decades, clinicians have been able to distinguish women who have a poor response to gonadotropin stimulation, significantly less oocytes recovered during in vitro fertilization (IVF), poorer quality embryos, and lower pregnancy rates from women with a similar age and infertility diagnosis. Many have suggested that these women demonstrate “early ovarian aging,” have ovaries “older than their chronological age,” or exaggerated FSH values during the follicular phase or during clomiphene citrate challenge tests [14, 15]. Terms such as “diminished ovarian reserve (DOR)” and “premature ovarian aging (POA),” and sometimes unexplained infertility, have been used to refer to women who have such a response but do not meet the criteria for POI [16–20]. It is difficult to determine if these patients are representing varying time points on a similar clinical spectrum of disease or whether they are entirely different patient populations. It is important to point out that impaired ovarian function as represented by POI is not a stable state. Therefore, it is best not to consider this condition as representing an irreversible decline in ovarian function, but rather an intermittent and unpredictable ovarian function that can undergo temporary remission. In other words, depending upon when in the course of her condition and to whom a woman presents for diagnosis, she might receive an ostensibly different diagnosis from each of three different clinicians. Thus, while it is worth noting that the relationship between DOR and POA and patients with POI warrants further investigation, the remainder of this chapter will focus specifically on women with overt POI, meaning loss of regular menstruation and the presence of menopausal level gonadotropins.
Etiologies
At the present time, most cases of POI remain without an etiologic diagnosis. Germ cell proliferation and depletion, follicular development, and the key cellular and molecular processes involved in normal ovarian function, let alone POI, are still in need of significantly more research. When a causal factor has been associated with the clinical phenotype, a sub-classification can be made in several ways. One way to create a framework for classification is by distinguishing the mechanism by which ovarian function diminishes: (1) A decrease in the initial primordial pool established in utero, (2) increased apoptosis/atresia of the follicles, or (3) failed follicular response or dysfunction [6, 10, 13]. The two major mechanisms are follicle depletion and follicle dysfunction, and several examples of each are listed in Table 5.3 [6]. Further discussion in this text will focus on the most common known or suspected causal factors of POI.
Table 5.3
Causes of spontaneous POI classified by two major mechanisms [6]
Mechanism and cause |
Comments |
Ovarian follicle dysfunction |
|
Signal defect |
Presence of ovarian follicles confirmed by biopsy; founder effect; rare disorder outside of Finland |
FSH-receptor mutation |
Ovarian follicles present on ultrasound examination; rare disorder |
G-protein mutation |
Secondary amenorrhea, elevated gonadotropin levels, and hypoestrogenemia that responded to gonadotropin therapy developed in patient with pseudohypoparathyroidism [11]; rare disorder |
Enzyme deficiency |
|
Isolated 17,20-lyase deficiency |
Ovarian follicles present on biopsy, “moderate ovarian enlargement” due to block in estradiol synthesis; rare disorder |
Aromatase deficiency |
Ovarian enlargement or hyperstimulation due to inability of the ovary to aromatize androstenedione to estradiol; rare disorder |
Autoimmunity |
|
Autoimmune lymphocytic oophoritis |
Antral follicles with lymphocytic infiltration into theca, primordial follicles spared, multifollicular ovaries; accounts for 4% of cases of 46,XX primary ovarian insufficiency; associated with evidence of adrenal autoimmunity |
Insufficient follicle number |
|
Luteinized graafian follicles |
Antral follicles imaged by ultrasonography in 40% of patients with idiopathic spontaneous 46,XX primary ovarian insufficiency; on the basis of histologic findings, at least 60% of antral follicles imaged in these patients are luteinized, a major mechanism of follicle dysfunction in these women [7] |
Ovarian follicle depletion |
|
Insufficient initial follicle number |
|
Blepharophimosis, ptosis, epicanthus inversus syndrome |
Mutation in FOXL2 is a mechanism of familial primary ovarian insufficiency, and disruption of the mouse gene causes a pervasive block in primordial follicle development; rare disorder |
Spontaneous accelerated follicle loss |
|
Turner’s syndrome |
Although a normal complement of primordial follicles is established in the ovary during fetal development, follicle loss through apoptosis is accelerated so that the store of primordial follicles is typically depleted before puberty; in oocytes, both X chromosomes must be present and remain active to prevent accelerated follicular atresia; the individual genes responsible for this ovarian syndrome have not been identified |
Environmental-toxin-induced follicle loss |
|
Industrial exposure to 2-bromopropane |
Exposure to cleaning solvent associated with primary ovarian insufficiency in 16 Korean women [12] |
Idiopathic
As discussed, most women with a diagnosis of POI will be in this category. This often leaves women as well as their clinicians frustrated and in pursuit of a significant number of screening and diagnostic studies to attempt to uncover any abnormal findings. In reality, some of these patients may have multifactorial causes, undiscovered iatrogenic, genetic, or environmental causes, or have some combination or partial findings of the rest of the etiologic sub-classifications identified in the following discussion.
Genetic
X Chromosome Abnormalities
As the genomics, proteomics, and similar related fields continue to expand, so does the understanding of the individual sex chromosomes, epigenetic modifications associated with reproduction, and the interactions between autosomes and sex chromosomes. Yet, we are likely only viewing the tip of the iceberg in our current state of knowledge. Although presently we can only identify a genetic cause in a minority of women, many women with POI may have underlying genetic and/or epigenetic etiologies of POI that are yet to be identified. For many years, testing was limited to karyotypes and identification of large chromosomal defects such as absence or partial absence of the X chromosome. We can now identify polymorphisms in the genome down to the single nucleotide with single nucleotide polymorphism (SNP) microarray analyses and associated genome wide association studies (GWAS), thanks to efforts like the Human Genome Project in 2003 and the International HapMap Project in 2005. Thus, there is great potential to accrue more diagnostic accuracy regarding the role of the X chromosome in the etiology of POI.
Abnormalities in the X chromosome have been one of the more well-researched areas in POI. It is clear that two copies of the X chromosome are required for normal ovarian function [21]. Women with classic Turner’s syndrome (45,X) nearly always have POI prior to the natural age of menarche. Women who present with secondary amenorrhea may actually be found to have mosaicism (usually 45,X/46,XX) on more detailed inspection. While this may seem counterintuitive due to the recognized phenomenon of X chromosome inactivation, many genes on the X chromosome actually escape inactivation and are thought to be critical to normal oocyte/ovarian function, especially for meiosis and folliculogenesis early in development. Both X chromosomes are active at the onset of meiosis in oocytes, during which time a reduced dosage of a particular gene product may have untoward effects. Furthermore, a careful study of X chromosome inactivation and its thorough sequencing has led to the concept that 20% or more of X-linked genes are expressed continuously from both X chromosomes [22–24]. Trisomy X (47,XXX), sometimes present in mosaic form, has also been associated with POI, although whether or not an X trisomy is related to a decrease in fertility and/or ovarian function is still debated [25, 26].
Submicroscopic gene deletions, duplications, translocations, and other mutations within the X chromosome have also been found at a much higher rate in women with POI [27–29]. The degree of haploinsufficiency for particular regions of the X, specifically Xp or Xq, may be responsible for variation in the age or symptomatic presentation of POI [13, 21, 30–32]. Some genes in what has been called the “critical region” of the long arm of X, Xq, may be affected by their relocation in the genome, as with a translocation. Whether this is due to dysfunction at the breakpoint or epigenetic mechanisms, such as chromatin structuring or promoter locations, has yet to be validated. Some of the genes in this region (often cited as Xq13-q21 or beyond) are POF1B, DIAPH2, and others [26, 33–37].
Two of the best characterized X-linked genes associated with POI are the fragile X mental retardation 1 (FMR1) and bone morphogenetic protein-15 (BMP-15) genes. Physicians and geneticists are particularly concerned with the associations between FMR1 and POI due to the constellation of phenotypes associated with abnormalities in the triple-repeat sequence in this gene. Severe expansion of the repeat sequence CGG in the FMR1 gene (in region Xq27) is responsible for one of the most prevalent genetic causes of mental retardation, fragile X syndrome. This full mutation occurs when over 200 CGG repeats are present in the 5′ untranslated region of the gene, causing hypermethylation and failure to transcribe the FMR protein. The normal number of repeats is less than 45 (and some consider 45–54 a gray zone of undetermined significance). The concern regarding POI lies in the premutation range, defined as 55–200 repeats. As the number of repeats increases, transcription and translation are altered. Transcription actually increases but effective translation of the protein diminishes [38]. It appears that excess mutated mRNA, which is unable to be translated, is what is toxic to the cell and this is maximized at a value of approximately 80 repeats. After 100 repeats, the risk of POI or associated FMR1 disorders may plateau or decrease [24, 39–42]. Premutations have been associated with psychologic and/or neurologic diagnoses such as autism, anxiety, hyperactivity, parkinsonian-like disorders, late onset tremor/ataxia in males, and other conditions [39, 43–45]. Concerns with the premutation also apply to future generations. Not only could a premutation expand to a full mutation during meiosis or subsequent development, but also offspring who carry a premutation are at risk for POI and, subsequently, an inability to reproduce [40, 41]. A thorough family history looking for mental retardation, dementia, tremor-ataxia, and other intellectual and psychologic disorders may suggest an increased risk of FMR1 premutation in a woman with POI, though testing should be offered regardless. Anywhere from 2 to 15% of women with POI could carry the FMR1 premutation, depending on the family history, resulting in a situation where the reproductive consequences could be significant if the patient is not made aware of the testing and implication of its results [6, 41, 44]. BMP-15 is a growth factor that appears to have a critical regulatory role in oocyte and follicular development. Its mutations are associated with or may predispose at least certain racial/ethnic subgroups of women to POI, but at present the clinical implications of this finding are unclear [46, 47].
Autosomal Gene Abnormalities
One of the classic genetic disorders associated with POI is galactosemia. The most common and severe form is the homozygous state where there is a complete lack of the enzyme galactose 1-phosphate uridyl transferase (GALT) and an inability to convert galactose to glucose. An affected individual presents in the first few days of life with significant morbidity and mortality if the condition is not recognized. Without the necessary enzyme, toxic precursors accumulate in large quantities and do significant damage to numerous cells, including those within the ovary [13, 48, 49]. There are several other enzymatic mutations and variants of disease severity that create more mild but significant forms of galactosemia. Galactosemia has been associated with an abundant number of mutations in the GALT gene and is inherited in an autosomal recessive fashion [50, 51]. Frustrating is the fact that homo- or heterozygosity for a particular allelic combination does not seem to predict phenotype sufficiently, including ovarian insufficiency timing and/or severity [52]. Women with classic galactosemia need close monitoring and follow-up with a specialized multidisciplinary team, including those with expertise in inborn errors of metabolism, dieticians, and endocrinologists. Most women with the classic form go on to develop ovarian failure, and some, like those with galcotokinase (GALK) mutation, do not have an increased risk. Yet, many women with other variants, and even those who have good dietary compliance, develop POI and it is difficult to predict future outcomes for individual patients [51, 52].
A second commonly cited autosomal abnormality is found on chromosome 3 within the FOXL2 gene. The FOXL2 gene is primarily expressed in the eyelids and granulosa cells in humans. The syndrome that results from a mutation in FOXL2 has been termed blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) and is linked with POI, primarily in type 1 BPES. The precise mechanism by which a FOXL2 mutation causes POI is still under investigation. One proposed process, based on animal models, is that a dysfunctional or truncated FOXL2 transcription factor causes a failure in the early stage pregranulosa cell’s ability to develop around and nourish a normal-sized primordial oocyte pool, which is likely reliant on FOXL2 expression in the female gonad [13, 53–55].
Numerous other genetic mutations have been implicated in POI. Among them are FSH receptor (FSHR) and inhibin alpha (INHA) [56, 57]. Anything that somehow affects gonadotropin regulation and action has subsequent consequences on ovarian function. Mutations in the actual subunits of FSH and luteinizing hormone (LH) have also been reported, although some would argue that these causes do not fit the definition of “primary” ovarian insufficiency at the level of the ovary [13]. The ataxia telangiectasia mutated (ATM) gene is a particular gene that has been implicated in causing oocytes to stall out in meiosis prophase I and then undergo apoptosis, due to a deficiency in the gene product [58, 59]. The BLM (Bloom syndrome) gene is somewhat similar, as it is a DNA repair gene that controls progression through the cell cycle and in a mutated form causes genomic instability [60]. This mutation has been linked with POI as well. Werner’s syndrome (WRN) gene may be another. Next is a family of eukaryotic initiation factor 2B (EIF2B) genes that were found to be mutated in eight patients with POI and leukodystrophy and related central nervous system abnormalities [61]. Other genes that have been reported include PMM2 (phosphomannomutase), AIRE (gene that causes autoimmune polyglandular syndrome (APGS) type I discussed further below), GDF9, NOBOX, and LDX8, among many others [6, 21, 32].
Other Gene Abnormalities
The oocyte is quite dependent on its mitochondrial energy production. Therefore, any mitochondrial dysfunction could be detrimental to oocyte health and predispose a woman to POI. One particular disorder, progressive external ophthalmoplegia, is linked with a mitochondrial DNA polymerase gamma (POLG) mutation, and it segregates with POI in certain families of women [62 ,63]. More mitochondrial abnormalities may be uncovered in the future as the biology of this field moves forward. It is likely that further research will uncover mitochondrial defects linked to POI, as the oocyte has more mitochondria than most cells in the body.
Certain steroidogenic enzyme defects result from other genetic mutations. Steroid acute regulatory protein (STAR) is required for mitochondrial membrane transport of cholesterol to start the production of steroids within the cell. A mutation within the STAR gene can result in a severe phenotype. Deficiencies such as 17α-hydroxylase or 17, 20-lyase deficiency and 20, 22-desmolase deficiency have also been associated with POI. Whether the steroidogenic similarities between the ovary and adrenal gland underlie the associated phenotypes remains unclear but is worthy of further research. Aromatase deficiency can also cause a block in the production of estradiol, although in this disorder, the ovaries enlarge due to continued follicular development [6, 13, 32].
Autoimmune Dysfunction
A portion of patients with POI appear to have an autoimmune-associated etiology [34, 64, 65]. There is a higher prevalence of autoimmune disease in women compared to men, and, more importantly, the association of POI with autoimmune dysfunction has been found in several studies to be significantly higher in women with autoimmune disease than that in the general population [66]. That said, the study of autoimmune conditions remains a very complex one, due to the non-Mendelian inheritance patterns and intricate multigenetic loci and environmental interactions. POI has been most commonly linked to autoimmune conditions within the thyroid and adrenal glands. Yet, it has also been associated with conditions such as dry eye syndrome, rheumatoid arthritis, hypoparathyroidism, diabetes mellitus, myasthenia gravis, and pernicious anemia [6, 13, 67]. A subset of such women may present with a polyglandular or syndromic disorder. Yet, women with isolated POI may still be at risk for future autoimmune conditions. Whether or not this implies an autoimmune oophoritis pathogenic process within the ovary, increased lymphocyte activation, or some other complex multifactorial process still needs further investigation. Potential autoantigen targets in the ovary are also a possibility that is a topic of current investigation.
Syndromic POI has been associated with APGS, of which there are four types (I–IV). Type I, due to a mutation in the AIRE gene, is referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), and the majority of patients with this mutation develop POI and adrenal insufficiency among other disorders [64, 68]. The AIRE gene is predominantly expressed in immune tissues such as the thymus. Such mutations may affect self-tolerance. While mutations in the AIRE gene may still be important in the pathophysiology of autoimmune dysfunction, some investigators have reported that the HLA subtype (especially class II) may be even more significantly associated with the phenotype than the AIRE mutation, or a combination of the two may be more detrimental [69].
For the remainder of women with POI, who do not have mutations in the AIRE gene or who are not HLA class II, an association between POI and other, more isolated autoimmune disorders appears to occur in a proportion higher than that can be accounted for by chance. Specifically, 2–10% of patients with POI have been found to have anti-adrenal antibodies, or more concerning, unrecognized adrenal insufficiency [64, 65, 67, 70, 71]. Due to the fact that POI can precede adrenal insufficiency, and the insidious, often asymptomatic course patients take before an adrenal crisis occurs, many physicians feel that screening for adrenal dysfunction is worthwhile in the POI population [65, 70, 72]. Thyroid autoimmunity is present in about 20% of women with spontaneous POI [6, 13, 64].
To many patients with POI as well as to clinicians, the discovery of an autoimmune etiology or an associated autoimmune disorder implies that the POI may be treatable or reversible by immune modulating therapies. Unfortunately, this is not the case. Most patients with POI, regardless of whether or not they have an associated autoimmune condition, will neither have biopsy-proven oophoritis, nor should they undergo such testing, and the risks of the various, immunomodulating therapies are often too significant to warrant therapy [10, 73, 74].
Iatrogenic/Environmental
Iatrogenic and environmental factors have been associated with POI. Cytotoxic therapies used in a variety of malignant and autoimmune conditions are one of the most prevalent causes. Alkylating agents have been the most ovarian-damaging chemotherapy agents in selected treatment regimens, and bone marrow transplant therapy is nearly 100% toxic to ovarian function [75, 76]. Hopefully, referral practices and public awareness are such that most young reproductive-aged patients are referred for consultations with reproductive endocrinologists prior to the administration of ovary-toxic therapies. Ionizing radiation, used to treat a number of cancers in the abdomen/pelvis, has also been demonstrated to cause ovarian dysfunction and/or failure. Surgical or procedure injury, such as a significant reduction of ovarian tissue or damage to the blood supply (i.e., unilateral oophorectomy, hysterectomy, and uterine artery embolization), is also a potential iatrogenic cause of POI [77, 78].
Numerous environmental factors have been implicated in the search for etiologic factors associated with POI. Tobacco smoke, stress, viral infection, and certain chemicals (2-bromopropane, 1, 3-butadiene, 4-vinylcyclohexane, and polycyclic aromatic hydrocarbons) are among those reported, some of which potentially mediate their effects through a Bax transcription pathway [79–83]. Finally, infiltrative or destructive conditions may also diminish ovarian function, such as with severe endometriosis [84].
Evaluation of Hypergonadotropic Amenorrhea
As discussed above, there is a myriad of ways a woman can present with POI. Disturbances in the menstrual cycle, especially amenorrhea or oligomenorrhea for 3–4 months, warrants an evaluation in nearly all women (with basic diagnostic testing including a pregnancy test, and if negative, FSH, thyroid stimulating hormone (TSH), and prolactin). Once a diagnosis of hypergonadotropic amenorrhea is made, the clinician should perform a basic evaluation, develop a treatment plan, and consider a referral as appropriate.
History
Most women with POI will have had normal puberty and menarche, a period of irregularities in their menstrual cycle, and ultimately a diagnosis of spontaneous POI. A small portion will present with primary amenorrhea. A very thorough personal and family history is very important for these women. Any symptoms that suggest estrogen deficiency (decreased libido, hot flashes, insomnia, vaginal dryness, etc.), environmental or iatrogenic insults to the ovary, or other related medical conditions should be sought after. A family history is very important and should include questions about other family members with POI, autoimmune conditions, and any neurologic and/or mental delay that could be related to the FMR1 gene or fragile X syndrome as discussed above. A percentage of women with autoimmune or FMR1 premutation etiologies of POI will reveal a significantly associated family history if asked the proper questions. When the potential exists for a genetic diagnosis for the POI, referral to a genetic counselor should be strongly considered. This will help establish a full pedigree and assures that the patient understands all of the implications of genetic testing for such conditions, especially FMR1. A social history that includes details about smoking, drinking, stress, and potential significant changes in weight or associated eating disorders are also important, although not necessarily associated with hypergonadotropic amenorrhea. Early (less than 45 years of age) or premature (less than 40 years of age) menopause in women relatives is a clue to genetic etiologies for POI.
Physical Examination
On physical examination, vital signs and general appearance of the woman should be assessed. Is there a subtle increase in skin pigmentation or vitiligo, or could there be orthostatic hypotension associated with asymptomatic adrenal insufficiency? Is there a neck goiter, lid lag, or fine tremor associated with thyroid disease? Does she have short stature, shield chest, or other suggestions of Turner’s syndrome? On the speculum and/or pelvic examination, vaginal atrophy could be noted visually or microscopically, and enlarged ovarian size as may occur in autoimmune oophoritis may be appreciated on bimanual examination [71].
Laboratory Evaluation
Laboratory examinations should always start with a pregnancy test, prolactin, and TSH in the evaluation of amenorrhea. In women with overt POI, the FSH values will generally be in the menopausal range, but should be confirmed with more than 1 month between testing. Since this disorder is associated with intermittent ovarian function, patients with a clear history suggesting hypergonadotropic hypogonadism may still have FSH values transiently in the normal range. In such cases, follow-up is needed to clarify the situation. It is not surprising to see FSH values wax and wane [10, 11]. Estradiol measurements are generally less than 50 pg/mL due to lack of follicular development, but could also vary with the course of the disorder. The utility of LH values remains controversial. Some would argue that assessment of follicular function may be better served with a transvaginal ultrasound. Others value the FSH:LH ratio in the diagnostic evaluation [7]. Of less controversy is the progestin withdrawal test. Most evidence would support that there is little gained by performing this test in the setting of a suspected diagnosis of POI. This is because the amount of estrogen priming needed to cause a positive progestin withdrawal may well be present in a woman with intermittent or early stage POI, and thus the false reassurance of a positive withdrawal may delay the diagnosis of significant hypogonadism. Over half of women with POI will have a withdrawal bleed [3, 5]. Therefore, the clinical utility of doing this is limited and potentially harmful in terms of ongoing bone loss related to estrogen deficiency [85].
Most expert opinions support obtaining a karyotype in women with POI. Over half of girls who present with primary amenorrhea, and approximately 15% of women with secondary amenorrhea due to POI have karyotypic abnormalities [8]. The reasons for obtaining a karyotype are several: (1) to determine if there is Y chromosome material present, which is associated with potential future malignancy; (2) to evaluate for loss or gain of an X chromosome, which may require further diagnostic studies and have health implications; and (3) to determine if significant levels of mosaicism exist. Further genetic studies should include testing for the FMR1 premutation due to the significant familial and reproductive impact of a potential expansion in the triple-repeat sequence as discussed above. Further molecular testing, to determine if there are submicroscopic or cryptic X chromosome mutations, translocations, deletions, or other abnormalities, is still limited in availability and their clinical usefulness is uncertain at the present time [4, 28].
Other laboratory testing includes an evaluation for potential associated autoimmune conditions. Up to 30–50% of women with POI may have some associated autoimmune disease [86]. Given that thyroid and adrenal disorders are fairly prevalent in women with POI and that there are effective therapies to treat them, they both merit evaluation. Initial work-up of amenorrhea should have included thyroid function studies, but if these have not been done, serum TSH and possibly free thyroxine (T4) should be ordered. Thyroid stimulating and thyroid peroxidase antibodies are also useful. Up to 20–30% of women with POI may have preexisting or will develop thyroid disease, most commonly hypothyroidism [70].
Testing for adrenal insufficiency or the potential to develop such a condition is important. While there are various ways to test for adrenal insufficiency, some may cause false positive or false negative rates. Testing for adrenal antibodies improves the pretest probability of other testing regimens (i.e., ACTH stimulation test, morning cortisol, aldosterone, and plasma renin activity) and, thus, should be performed first, followed by the other testing when clinically indicated [65, 87]. Approximately 5% of patients with POI who are asymptomatic for any adrenal disorder will end up testing positive for adrenal antibodies and approximately 3% will have unrecognized adrenal insufficiency. Detection of these women can ultimately be life-saving if discovered prior to a crisis, which can be precipitated during an elective surgery or trauma [65, 70]. Adrenal cortex and 21-hydroxylase antibodies are the assays most reliable for testing. Predictive models have been made to determine the 5-year probability of developing autoimmune Addison’s disease based on age, gender, adrenal function, antibody titers, and co-existing disease [88]. Such a predictive model may help guide physicians regarding the difficult decisions for determining monitoring intervals and follow-up.
Finally, testing for diabetes-related illnesses may be useful due to the risks of untreated disease and minimal cost, although only a small number of women will test positive (2%). Using either a fasting glucose or a 2-h glucose tolerance test is acceptable, although rarely a 2-h test will identify those with intolerance who have a normal fasting value. Testing for pernicious anemia or hyperparathyroidism, with either a vitamin B12 or calcium level, respectively, may not be useful in asymptomatic women [70]. Testing for ovarian antibodies is generally not justified due to their nonspecific nature and need for more research. A number of other, more obscure conditions that have been reported in association with POI can be excluded by performing a serum chemistry profile and CBC with indices [70].
Initial imaging considerations include a pelvic ultrasound to evaluate both the uterus and ovaries, and a bone density test. A significant number of women with POI are found to be osteopenic, and possibly even osteoporotic at the time of diagnosis, and have reduced bone mineral density compared to controls [6, 8, 85, 89]. Such findings not only guide calcium (1,200 mg elemental calcium/day), vitamin D (800 IU/day), exercise, and smoking cessation counseling but also highlight the need for hormone replacement therapies unless contraindications exist.
Emotional Assessment
POI affects a woman’s physical health and wellness, yet often the most difficult and profound aspect for women and their caregivers is dealing with the emotional response to the diagnosis and treatment of this chronic condition. The diagnosis usually comes as a shock, as it is often unexpected and unanticipated when undergoing medical evaluation. Living with the condition can be life-changing, as a woman’s view of her place in the world is irrevocably altered by this tremendous threat to her self-concept of her femininity and its ties to her fertility potential [90]. Frequently, the most devastating realization for women is impaired fertility and other health issues may be minimized. As a consequence, care must focus on both the physical and emotional needs of women with POI. This aspect of care begins with the diagnosis itself.
Delivering the Diagnosis
How the diagnosis of POI is communicated can influence a woman’s emotional response to her health, perception of self, treatment compliance, quality of life, and overall satisfaction with care. One study found that almost half the women interviewed received the diagnosis from their physician over the telephone or by message, and three-quarters reported their doctor spending 15 min or less in communicating the information. The result was that over 70% felt unsatisfied or very unsatisfied with this communication and 89% described feeling emotionally traumatized after hearing the diagnosis. Patients were most satisfied when they felt prepared to hear the diagnosis, perceived the clinician as knowledgeable, felt the clinician spent sufficient time with them, and that the physician was sensitive to their emotional needs [91].
When delivering the diagnosis, steps need to be taken to ensure that the patient is able to hear the news in a non-traumatizing way and know that she will be assisted in getting appropriate help and support in dealing with POI. Buckman has written a six-step protocol for breaking bad news to patients which recommends the following [92]:
· Get started with a private physical setting to talk
· Find out how much the patient knows
· Find out how much the patient wants to know
· Share the information using an agenda developed before you sit down with the patient, so that you have the relevant information at hand
· Respond to the patient’s feelings, “Could you tell me a little more about how you’re feeling?”
· Plan and follow through by outlining an explicit step-by-step approach that can be carried out
From this perspective, it is ideal to meet physically with a patient, in a private place, and with sufficient time to talk when going over the diagnosis. Physicians need to be able to acknowledge patients’ emotions and respond with patience and empathy. In addition, it is helpful to have written materials and resource information about POI available to give, so that the patient does not go home “empty-handed.” There is a need to develop evidence-based approaches to provide emotional support and guidance to women experiencing the emotional sequelae associated with POI.
Psychologic Impact
While learning the diagnosis can be traumatic, living with POI can cause women significant, long-term distress and suffering. Using language that can be interpreted as judgmental, such as POF or “premature menopause,” may reinforce a sense of stigma and defectiveness, and negatively affect body image. Women with POI describe feeling old, unfeminine, less healthy, empty, and worthless [91]. Over time, patients with POI have been shown to have reduced self-esteem, increased shyness, diminished perception of social supports, increased social anxiety, and more symptoms of depression and anxiety compared with control women [4, 93, 94]. The emotional suffering felt by women with POI is often experienced in isolation, as they may have difficulty in identifying people who they believe can truly understand their feelings or may feel such shame, embarrassment, and/or sense of defectiveness that they are unable to reach out to others. Thus, their sense of self and relationships with others can be profoundly negatively affected. Care should, therefore, include referrals for psychologic assistance, including counseling for women, their partners, and families. There is a need for evidence-based interventions to help these women cope with the emotional sequelae of this disorder. Not all women find the existing lay-led support groups beneficial, and some describe them as harmful.
The awareness of impaired fertility is often the most painful aspect of learning about POI. It is well documented in the literature that infertility is a major life crisis, generating significant sadness, distress, and grief [95]. The losses associated with infertility are multifaceted and, yet, uniquely personal to each woman as they reflect her dreams and hopes for the future: a wish for child/family, status in the community, health, passing on of genes and knowledge, and the experience of pregnancy, among others [96]. Grief is the emotional response to the loss of a significant relationship and often includes such feelings as shock, disbelief, anger, sadness, depression, guilt, shame, blame, and hopefully, eventually, acceptance. When the loss is invisible or intangible to others, as in the desired child, it is even more difficult to grieve [97]. It is helpful for the physician to “name” the sequelae of emotions as “grief,” thereby communicating the emotional response as normal and giving permission to grieve and mourn as one is allowed to do with other more tangible losses [98].
Patients often feel urgency in trying to achieve a pregnancy when diagnosed with POI. Because a small percentage of women will become pregnant spontaneously, patients may find themselves in an ambiguous position of “Am I infertile or not?” Thus, they may embark on a journey to find ways to become pregnant quickly, a journey that often leads to the high-tech world of ART. As their life plans are altered, family building, in their view, must now become deliberate, determined, and costly in terms of finances, time, and emotional energy. Patients are often willing to undergo painful, expensive, and, as yet, unproven treatments in the hopes of restoring ovarian function and achieving pregnancy. These therapies carry a risk of interfering with spontaneous conception that can occur, and patients need to be advised about the overall ineffectiveness of these often expensive, unproven interventions [98].
It is important to keep in mind that not all individuals desire to get married or raise children. For those who have this desire, family-building options include egg or embryo donation, adoption, or the hosting of foster children. The passage of time can be important in helping patients arrive at these options, as it allows them the opportunity to grieve and come to terms with the loss of a hoped-for biologic child. When physicians offer donor egg or adoption precipitously after giving the POI diagnosis, it can circumvent grief and potentially cause problems later. Thus, patients avoid doing the emotional work necessary to heal the losses of infertility. Alternative family building does not cure the feelings of infertility, although it does fill the space of the longed-for child. Discussion with patients about choices must go beyond biologic parenthood and alternative family building, and include the achievement of other life goals and purposes, such as career, hobbies/interests, and spirituality [4].
Sexual Impact
The impact of POI on a woman’s sexual identity, sexual functioning, and sexual relationship is another aspect of her emotional health that needs to be addressed by caregivers. The earlier in age the POI is identified, the more complex is the impact on all dimensions of sexuality [99]. Sexual identity is especially vulnerable when POI disrupts the normal process of development in an adolescent girl, affecting attachment needs and the ability to achieve autonomy [100]. Even before receiving the diagnosis, symptoms related to POI, such as hot flushes, night sweats, irritability, vaginal dryness, and mood disturbance, may have challenged a woman’s sense of stability and affect her sexual functioning. After learning about POI, the loss of the potential to reproduce may impair motivation and desire for sexual activity, as she may feel “What’s the use?” The susceptibility to psychosexual distress from POI is greater in women who wish for children and lower in those focused on their professional and social achievements [99].
As in all sexual dysfunction, sexual difficulties for women with POI need to be identified by the physician as a disorder of sexual interest or desire; the ability to be aroused; difficulty in achieving orgasm; and/or sexual pain. Treatment methods for sexual dysfunction, as well as to general health-related matters in POI, should take a multidisciplinary approach and may include a gynecologist (HR treatment), urologist (male partner’s sexual dysfunction), psychiatrist (psychopharmacologic treatment of affect disorders), sex therapist (behavioral treatment), couple’s therapist (relationship issues), individual psychotherapist (personal issues), and/or physical therapist (pelvic floor issues) [99]. Hormone therapy (HT) may be helpful in arousal and desire disorders. Psychosexual behavioral treatments and couple’s and/or individual therapy are useful in many areas. Women and their partners need to understand how POI can affect feelings and functioning (sexually and otherwise), and be given appropriate medical therapies and referrals for psychosocial resources.
Treatment
Genetic Counseling
Genetic counseling is an important part of the diagnostic and treatment strategies for women with POI. This is especially critical when women are found to have karyotypic abnormalities and/or FMR1 premutations. Patients need to be informed about the implications of an abnormal karyotype so as to give informed consent for the testing. In situations with high pre-test probability of a positive test, it is best to offer genetic counseling before actually performing the tests. Such findings have significant implications for each individual woman’s reproductive, genetic, and family health.
Family Planning
While much discussion centers on infertility, it is important to note that POI can be transient, and spontaneous remission and/or conception can occur. Therefore, if pregnancy is not desired, appropriate contraception must be discussed. Furthermore, case reports exist of women with POI ovulating and conceiving on oral contraceptive pills [101]. Oral contraceptives have not been proven effective in this specific population of women. This concern, combined with the fact that these women have menopausal FSH levels that may not be adequately suppressed by oral contraceptives, makes it prudent for women with this condition to use a barrier method or intrauterine device.
As discussed, while a diagnosis of POI implies a significant decrease in ovarian reproductive and endocrine function, it does not always imply cessation of function, and 5–10% of women with POI may still spontaneously conceive. General pre-conceptual health and individual medical and genetic counseling should take place prior to conception, as with any woman hoping to conceive. Regardless of the possibility of spontaneous conception, most realize that the chance of non-assisted conception is low and many, but not all, seek out ART. It should be remembered that many women have cultural or religious objections to ART. However, as discussed in the emotional health section, many do feel a need to attempt aggressive therapies such as IVF with or without egg or embryo donation to make every attempt at conceiving a biologic child.
Finally, as genetic and diagnostic technologies as well as medical treatments and interventions continue to advance, so may the abilities to predict the onset of POI and those who may be at significant risk for such a diagnosis in the future. We are already at a time when we can predict the possibility of POI after systemic cytotoxic therapies in certain cancers and autoimmune diseases. Thus, the research and advances in fertility preservation have been at the forefront of many discussions surrounding ovarian function and/or reserve. Cryopreservation of sperm has successfully been established for decades, especially with the advancement of intracytoplasmic sperm injection, allowing the utilization of as little as a single sperm to achieve a pregnancy. In the same regard, cryopreservation of embryos has also been fairly well accepted as a standard option for fertility preservation, with a success rate surrounding 30% per frozen embryo transfer cycle, although many factors must be considered. The issue for most women with POI is that they may not be married or have a partner to consider embryo freezing. While they may use donor sperm, this option is often not acceptable to some women.
More recently, efforts have been directed toward improving oocyte and ovarian tissue cryopreservation [102]. Although these technologies are improving, they are still considered experimental at most institutions, since very few pregnancies have resulted from thawing of ovarian tissue and oocytes. Moreover, they have not been tested or have been found to be of little use in women who already have a severely compromised oocyte supply. Thus, for most women with POI, regardless of stage, these treatments are not an option at the present time.
Significant controversy still involves the potential success rates and the best mechanisms for freezing, thawing, and re-implanting ovarian tissue, whether it is cortical strips or portions of the whole ovary [103–109]. Even more rare is the very few reports of ovarian transplantation in monozygotic twins discordant for ovarian failure [110]. Thus, physicians are often left with an ethical dilemma when counseling and encouraging patients regarding fertility preservation in many situations. The most important thing is honest and informative counseling, so patients can weigh all of their options. Technology could significantly improve in the future and if the ability to foresee future POI becomes possible, along with fertility preservation improvements, this may become an established and routine option for young women facing the development of iatrogenic POI.
Medical Therapy
Although level I evidence regarding the effectiveness of HT in women with POI is lacking, nearly all expert opinions support the use of HT until at least the natural age of menopause in these women, unless significant contraindications exist [111, 112]. Beyond symptom control, long-term bone and cardiovascular health are at the top of the list of concerns that physicians have when determining whether and how much HT to administer. There have been a handful of research studies that demonstrate significant increased morbidity and mortality in women with early menopause [6, 113–115], which has led to a concern that hormones are warranted in this younger age group of women. A physiologic replacement dose of estradiol in combination with a cyclic progestin is preferred [6]. A dose of 100 μg/day, delivered by skin patch, achieves physiologic, mid-follicular phase estradiol levels in these women. Medroxyprogesterone acetate 10 mg/day for 12 days each month should be taken to induce monthly withdrawal bleeds and to transform the endometrium fully to a secretory phase when given in conjunction with a full replacement dose of estrogen [116, 117]. If a menses does not occur, a pregnancy test should be obtained, and the hormones stopped if positive. Monthly progestin administration reduces the risk of endometrial hyperplasia, and with long-term administration, the development of endometrial carcinoma. The endometrial effects of oral micronized progesterone have not been adequately evaluated at the dose of estrogen recommended as replacement for these young women [118].
Decisions regarding androgen replacement therapies are even more difficult, and there is a need for more research before such treatment can be recommended. Similar to treatment with estrogen and progestin, specific studies on younger patients with POI are lacking, and applying findings from older patients with a natural, rather than pathologic, cessation in ovarian function has problems [119–125]. All such therapies deserve special consideration and collaboration with specialists when appropriate.
Preventative Therapy
The dominant issue of infertility can preclude adequate focus on all the important potential long-term adverse health consequences of diminished ovarian function. Yet, the ovary is important as an endocrine organ as well as a reproductive organ. A 59-year-old woman with natural menopause and a 19-year-old woman with POI are different patients, although both have important health considerations. General health counseling may partially be the same: exercise, good nutrition, smoking cessation, calcium and vitamin D supplementation, and good control of concomitant medical illnesses. A bone density screening test is just as important in the young woman with POI as it is in the older naturally occurring menopausal patient due to the prevalence of osteopenia and, occasionally, osteoporosis [85, 89]. Whenever the ovary ceases or significantly diminishes production of estrogen, progesterone, and androgens, there is associated bone loss over time [10, 98, 126].
Since the advent of the Women’s Health Initiative and subsequent studies, there has been great reluctance to utilize HT for preventative health. What is often unrecognized by patients is that nearly all studies on estrogen and progestin (and androgen replacement) therapy have been performed on women who are significantly older (often much older than even 50 years of age), and naturally or surgically menopausal. The applicability of these studies to women with POI is unknown. Fear in young women with POI regarding enhanced cardiovascular risk, cancer, or thrombosis with the use of HT may be completely irrelevant as women with normal ovarian function in their 20s, 30s, and even 40s have hormones being produced endogenously, and non-orally administered HT is simply replacing what would otherwise be present. HT after the natural age of menopause, in considerably higher dosages, and in the presence of concomitant thrombotic or significant medical conditions, warrants individual and more specific consultation with medical providers.
Finally, women with POI are at risk for developing other autoimmune and endocrine disorders [6, 13, 64, 70, 127] and, therefore, merit surveillance. Most commonly, POI-associated thyroid and adrenal disorders will emerge over time. The current literature supports periodic screening for some autoimmune-associated conditions as discussed above. Decisions about when to repeat testing if normal at baseline as well as follow-up of slightly abnormal testing or antibodies predicting future disorders are more complicated and need further research.
Back to the Vignette
The woman in the vignette illustrates one possible presentation of a woman with POI. This particular patient scenario was chosen to highlight the vague and unanticipated symptoms in an otherwise healthy young woman. Many clinicians and often the patient herself might attribute her secondary amenorrhea to stress or weight loss, or might only search for thyroid- or prolactin-associated disorders. Such a patient could have previously been to several physicians who disregarded some of her non-specific complaints and ignored the changes in her menstrual cycle. Her progestin challenge test yields minimal to no information useful for diagnosis, and may in fact delay her diagnosis. Once the diagnosis of POI is confirmed by a second menopausal FSH test 1 month later, significant counseling must be undertaken regarding all of the issues addressed in this chapter. She has a significant family history for various autoimmune conditions and warrants a thorough evaluation for any associated autoimmune disorders. Her smoking is a well-established environmental factor that could further diminish her reproductive years, so counseling regarding cessation of smoking is important. Genetic counseling with FMR1 testing and a karyotype is indicated, due to her POI diagnosis, family history of mental retardation, and her small stature. Counseling regarding her family plans should include an assessment of the overall likelihood of a spontaneous conception (5–10%). She may elect to avoid advanced techniques of reproduction for personal reasons and search out other solutions for becoming a parent, or she may request immediate ART. The clinician should help guide her through these decisions with appropriate outcome information and avoid being judgmental. Her desire for fertility and psychologic needs (sexual health, infertility, and the emotional impact of the diagnosis) are extremely important, and require time, a sensitive physician, and a multidisciplinary approach.
Having guided the patient through the initial diagnosis and work-up, the physician has a responsibility to consider long-term health implications of a diagnosis of POI. All of these things warrant time, patience, discussion, and will likely take place over numerous office visits. Appropriate referrals to subspecialists should be considered as issues are identified. Hopefully, as awareness and treatment options (such as genetic, immunoassay, fertility preservation, and medical therapies) continue to improve, patients, such as the one described here, will find their search for answers more easily navigated and the likelihood of fertility more promising.
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