Expanding our knowledge of premature ovarian insufficiency

Premature ovarian insufficiency (POI) has received increasing attention over the past two decades as it has become apparent that this is not an extremely rare disorder. Our thoughts about this disorder have evolved, just as has the name given to the disorder itself. As noted by others, Fuller Albright first used this term in 1942. Since then, it variously has been called the “resistant ovary” or “Savage” syndrome, premature ovarian failure, hypergonadotropic hypogonadism, primary hypogonadism, and hypergonadotropic amenorrhea (1Rebar R.W. Premature ovarian failure.Obstet Gynecol. 2009; 113: 1355-1363Crossref PubMed Scopus (132) Google Scholar). Regardless of the name, this disorder is characterized by elevated levels of gonadotropins, low levels of estradiol, amenorrhea (for most), and markedly reduced fertility. Despite scattered early reports, historically, many investigators and clinicians did not believe the ovaries could “fail” prematurely. The concept gradually caught traction when immunoassays for gonadotropins became widely available in the 1970s and was bolstered when individual case reports documenting the existence of the disorder emerged. This problem gained a full foothold in the clinical community when the possibility of “reversibility” in isolated individuals was realized. In 1990 we reported one of the first large series of women presenting with POI, noting the 115 affected individuals were surprisingly diverse (2Rebar R.W. Connolly H.V. Clinical features of young women with hypergonadotropic amenorrhea.Fertil Steril. 1990; 53: 804-810Abstract Full Text PDF PubMed Google Scholar). Only included were women younger than 40 years of age with at least 4 months of amenorrhea and levels of follicle-stimulating hormone (FSH) ≥40 mIU/mL on two occasions 4 or more weeks apart. Most presented with absent or irregular menses or infertility, some presented only with symptoms of estrogen deficiency, and a few women remained largely asymptomatic. In that retrospective series, withdrawal bleeding in response to exogenous progestin occurred in more than 48% of women, and at least one ovulation (based on elevated serum progesterone levels followed by menses, a secretory endometrial biopsy, or a confirmed pregnancy) was documented in just less than 25% of women. Despite the occurrence of ovulation, pregnancy resulted in only 8.1% of those included in the cohort. The diversity we described in 1990 has now been reported time and again. Yet even with our evolved understanding of the concept of “ovarian reserve,” individuals with this disorder often remain incorrectly diagnosed for several years. We and others have attempted to list and categorize the various causes of POI, and a striking feature of this disorder is that no single cause predominates among those women affected (1Rebar R.W. Premature ovarian failure.Obstet Gynecol. 2009; 113: 1355-1363Crossref PubMed Scopus (132) Google Scholar). Early recognized causes included women with autoimmune syndromes, particularly of the thyroid gland and adrenocortical tissues, as well as those with profound ovarian damage resulting from chemotherapy and/or irradiation for various malignancies. It is now probable that most cases are due to genetic mutations, even if most cases are classified as “idiopathic” after evaluation. Karyotypic abnormalities, single gene mutations, and multifactorial polygenic inheritance all account for some causes of POI. Individuals with X chromosomal abnormalities constitute one of the larger proportions of affected patients, and one of the more common causes of POI is among women who carry the Fragile X premutation. Because of the malignant potential of Y-containing gonadal tissue, it also is important to exclude the presence of any Y chromosomal material. Many other mutations have been identified, but few involve large numbers of individuals. Unfortunately, even with the biomarkers currently available, we still are unable to identify the 5%–10% of women with POI who have the potential for spontaneous pregnancies. For women diagnosed with POI, identifying the presence of follicles does not guarantee future ovulations or pregnancy. Controlled ovarian hyperstimulation also does not appear to increase the chances of successful pregnancy significantly, so many women with POI turn to in vitro fertilization using donor oocytes (1Rebar R.W. Premature ovarian failure.Obstet Gynecol. 2009; 113: 1355-1363Crossref PubMed Scopus (132) Google Scholar). Pregnancy should be contemplated only after extensive counselling, particularly in women with Turner syndrome and in those who carry the FMR1 gene premutation (1Rebar R.W. Premature ovarian failure.Obstet Gynecol. 2009; 113: 1355-1363Crossref PubMed Scopus (132) Google Scholar). Collectively, the search for additional biomarkers continues in the hopes of helping a larger proportion of women with POI increase their fertility and bear their own children if they so desire. Current markers used to evaluate ovarian function in women with POI are produced by the ovarian granulosa cells and include estradiol, antimüllerian hormone, and inhibin B. Antral follicle count within both ovaries on transvaginal ultrasound examination also is used to assess ovarian function. A new study conducted by Chinese investigators, who have been instrumental in identifying some of the mutations associated with POI, suggests that measurements of serum insulin-like factor 3 (INSL3), produced by the theca cells, might be a new biomarker useful for evaluating the progression and status of women with POI (3Zhu C. Luo W. Li Z. Zhang X. Hu J. Zhao S. et al.A new theca-cell marker INSL3 associated with premature ovarian insufficiency.Fertil Steril. 2021; 115: 455-462Scopus (3) Google Scholar). Originally identified as a hormone secreted by testicular Leydig cells, this novel peptide subsequently was found in the theca interna cells surrounding the developing follicle as well as in corpora lutea (4Ivell R. Anand-Ivell R. Insulin-like peptide 3 (INSL3) is a major regulator of female reproductive physiology.Hum Reprod Update. 2018; 24: 639-651Crossref PubMed Scopus (22) Google Scholar). Insulin-like factor 3 has been shown to bind specifically to a unique G-coupled receptor, relaxin-family peptide receptor 2 (RXP2), which is expressed in oocytes of growing follicles, luteinized granulosa cells, and in cells of the theca interna, suggesting that this system has both paracrine and autocrine actions and plays a role in the two-cell theory developed to account for follicular maturation. Also, INSL3 has been shown to induce expression of growth differentiation factor 9 by the oocyte. Mice deficient in INSL3 have a number of reproductive problems, including abnormal estrous cycles, reduced ovulation, increased follicular atresia and apoptosis, decreased litter size, and infertility. The addition of a new marker that is specific for theca cells to evaluate ovarian status and reserve is appealing. None of the markers investigated to date, alone or in combination, is absolutely diagnostic of sterility in individuals with POI or even diminished ovarian reserve. The study provides evidence that INSL3 is associated negatively with FSH levels and associated positively with antimüllerian hormone, inhibin B, antral follicle count, and even testosterone levels. Moreover, INSL3 levels were good predictors of diminished ovarian reserve as determined based on elevated FSH and reduced estradiol levels. This new study is an extension of earlier observations that INSL3 levels were reduced in women with infertility, including those with POI (4Ivell R. Anand-Ivell R. Insulin-like peptide 3 (INSL3) is a major regulator of female reproductive physiology.Hum Reprod Update. 2018; 24: 639-651Crossref PubMed Scopus (22) Google Scholar). The serum concentrations of INSL3 reported in the current study (3Zhu C. Luo W. Li Z. Zhang X. Hu J. Zhao S. et al.A new theca-cell marker INSL3 associated with premature ovarian insufficiency.Fertil Steril. 2021; 115: 455-462Scopus (3) Google Scholar) are significantly higher than those reported previously for females of any mammalian species, but, regardless, when taken on a percentage basis, it would appear that INSL3 decreased about 25% in women with biochemical POI and 50% or more in women diagnosed with POI. Interestingly, elevated luteinizing hormone (LH) levels associated with the LH surge suppress the theca-driven production of INSL3 in cattle (4Ivell R. Anand-Ivell R. Insulin-like peptide 3 (INSL3) is a major regulator of female reproductive physiology.Hum Reprod Update. 2018; 24: 639-651Crossref PubMed Scopus (22) Google Scholar), raising the possibility that reductions in INSL3 in women with POI could be a mere consequence of the chronically elevated concentrations of LH (and FSH) trying to “kick-start” the nonfunctioning ovary. From a physiological perspective, it is not surprising that theca cell function is impaired also in the follicles of women with POI. Reduced serum levels of INSL3 were correlated with reduced serum levels of testosterone, and, although they did not measure androstenedione, the authors purported that reduced INSL3 could lead to the impaired ovarian steroidogenesis indicative of this disorder (3Zhu C. Luo W. Li Z. Zhang X. Hu J. Zhao S. et al.A new theca-cell marker INSL3 associated with premature ovarian insufficiency.Fertil Steril. 2021; 115: 455-462Scopus (3) Google Scholar). Our limited knowledge of the INSL3-relaxin-family receptor 2 (RXP2) pathway in ovarian steroidogenesis suggests this is a plausible conclusion, but levels of INSL3 in the follicular fluid were not significantly different among the three groups of women examined in this study, forcing us to ponder other possible effects of reduced circulating levels of INSL3 in women with POI. One glaring possibility is that the reduced serum concentration of INSL3 could be associated with the reductions in bone mineral density associated with this disorder. Insulin-like factor 3 has been shown to bind with the relaxin-family peptide receptor 2 in osteoblasts to promote anabolic remodeling and building of bone (4Ivell R. Anand-Ivell R. Insulin-like peptide 3 (INSL3) is a major regulator of female reproductive physiology.Hum Reprod Update. 2018; 24: 639-651Crossref PubMed Scopus (22) Google Scholar); therefore, reductions in both INSL3 and estradiol would exacerbate bone loss and lead to osteoporosis, a well-established problem in POI. Over the years, treatment for individuals with POI has been clarified (1Rebar R.W. Premature ovarian failure.Obstet Gynecol. 2009; 113: 1355-1363Crossref PubMed Scopus (132) Google Scholar, 5Webber L. Davies M. Anderson R. Bartlett J. Braat D. et al.The ESHRE Guideline Group on POIESHRE guideline: management of women with premature ovarian insufficiency.Hum Reprod. 2016; 31: 926-937Crossref PubMed Scopus (502) Google Scholar). Puberty should be induced slowly with exogenous estrogen in those individuals who fail to mature. Systemic estrogen replacement should be provided to young women with this disorder at least until the normal age of menopause, and an exogenous progestogen should be added to those with a uterus. Controversial is the addition of exogenous androgens because efficacy and safety have not been established; however, it has been documented that women with POI have much lower levels of androgens than do age-matched healthy women (1Rebar R.W. Premature ovarian failure.Obstet Gynecol. 2009; 113: 1355-1363Crossref PubMed Scopus (132) Google Scholar, 5Webber L. Davies M. Anderson R. Bartlett J. Braat D. et al.The ESHRE Guideline Group on POIESHRE guideline: management of women with premature ovarian insufficiency.Hum Reprod. 2016; 31: 926-937Crossref PubMed Scopus (502) Google Scholar). Still, it is estrogen replacement alone that alleviates the symptoms in most women with POI, and, therefore, the development of a new biomarker and/or therapy would be a welcome addition to the clinical arsenal used to diagnose and treat women with this disorder. It appears that the human ovaries can respond in only a limited number of ways to exogenous stimuli and insults and even to genetic mutations. Follicles may be reduced in number or undergo accelerated atresia to result in POI. Polycystic ovaries may develop in response to excess androgens from any source. Follicular development ceases if there is insufficient gonadotropic stimulation, as may occur in hypothalamic-pituitary disorders. Serum markers may assist in identifying the source of the problem but whether the addition of INSL3 will add significantly to our clinical armamentarium remains to future studies. Although the authors suggest that measurement of INSL3 will predict progression of POI, this strikes us as overly optimistic. There are at least two subsets of theca cells in the ovary and the role of the INSL3-RXP2 pathway in the ovary is still relatively novel. This new marker likely will be most useful as a new tool to aid in learning more about the pathophysiology of the ovary. This was an innovative study that should open new avenues to investigate steroidogenesis, follicular development, and consequences of POI. Whether INSL3 will have clinical utility for patients with POI or in the evaluation of normal ovarian senescence remains to be determined. New theca-cell marker insulin-like factor 3 is associated with premature ovarian insufficiencyFertility and SterilityVol. 115Issue 2PreviewTo characterize circulating insulin-like factor 3 (INSL3) in different stages of ovarian insufficiency and its role in the evaluation of premature ovarian insufficiency (POI). Full-Text PDF