Premature ovarian insufficiency - fertility challenge

J H Check

Premature ovarian insufficiency - fertility challenge

Check JH

Published April 2014 Minerva Ginecologica

PMID 24848073

Read our synopsis

RRM Academy Synopsis

Premature ovarian insufficiency can reverse temporarily with ovulation

A 2014 review by one author reports that ovulation occurred in about 2 out of 10 attempted cycles after high FSH was lowered in 100 women with early ovarian failure. It also cites case reports and randomized trials.

Key Findings

In 100 consecutive women with hypergonadotropic amenorrhea and estrogen deficiency, ovulation occurred in approximately 20% of attempted cycles. Overall, 37% of the women ovulated.
Among 91 women on the estrogen-hMG method, 19 conceived (20.8%). Of the 34 women made to ovulate, 19 conceived (56%). The paper reports a 50% miscarriage rate in the series.
The 1984 report of the method treated 5 patients. Three responded, and 2 of them delivered live babies.
A placebo-controlled randomized trial found ovulation in 3 of 15 women on a GnRH agonist (20%) and in none of 15 controls. The trial lacked the power to make this difference significant.
Among lymphoma patients treated with alkylating agents, 34% developed premature ovarian insufficiency, against 3% of those treated without alkylating agents.

Interpretation

The paper is a narrative review by an author who advocates the FSH receptor restoration technique. Its main evidence is a non-randomized case series, plus case reports. The paper cites one randomized trial with no benefit and another it reads as supportive. The expert review it quotes found no trial with enough power. The series included women up to age 47, and the paper says results would probably be higher in younger women alone. The author says chance ovulation seems unlikely in women with years of amenorrhea. The endometriosis section rests on one review and a conference report of 15 women.

RRM Context

Restorative reproductive medicine asks why ovulation stopped and works with the woman's own hormonal signals. The review applies that aim to premature ovarian insufficiency and to a woman's own eggs. The reviews it quotes offer donor eggs or adoption. Protocols differ among clinicians and are not described here. Excision by a skilled surgeon is the surgical standard for endometriosis.

Our editorial summary of this paper, not the article's abstract.

Abstract

Premature ovarian insufficiency, defined as amenorrhea with estrogen deficiency in a woman younger than 40 associated with a serum follicle stimulating hormone (FSH) >35 mIU/mL, can be temporarily reversed with ovulation achieved resulting in live delivered pregnancies. Though this may occur spontaneously the frequency of ovulation can be considerably increased by various techniques of lowering the elevated serum FSH level and thus up-regulate down-regulated FSH receptors in the granulosa-theca cells. This can be accomplished by either suppressing FSH release from the pituitary by negative feedback through high dose estrogen or by suppressing FSH production by inhibiting the gonadotropin releasing hormone (GnRH) by either using GnRH agonists or antagonists. The estrogen method is the technique of choice because it is much less expensive than GnRH analogues, and helps stimulate cervical mucus and endometrial development. Ethinyl estradiol is the preferred estrogen because it does not contribute to the measurement of serum estradiol and thus allows proper monitoring of follicular maturation. Sometimes exogenous gonadotropins are needed as a boost but the dosage should be low so as not to down-regulate FSH receptors again. The technique is referred to as the FSH receptor restoration technique. Progesterone should be supplemented in the luteal phase. Physicians should be cognizant of trying to help prevent premature ovarian insufficiency by judiciously choosing less gonadotoxic cancer treatment alternatives that are equally efficacious. Also surgery for ovarian endometriomas should be performed only when absolutely necessary.

By this author

Standards in semen examination: publishing reproducible and reliable data based on high-quality methodology

Björndahl L et al., 2022 Human Reproduction

Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, and the International Standard ISO 23162:2021. With these tools, we propose that authors should be instructed to follow these laboratory methods in order to publish studies in peer-reviewed journals, preferable by using a checklist as suggested in an Appendix to this article.

Ovarian Hormones · Progesterone

Maximizing Correction of Infertility with Moderate to Marked Diminished Egg Reserve in Natural Cycles by Up-Regulating Follicle Stimulating Hormone Receptors

Check JH et al., 2022 Gynecol Reprod Health

Many infertility specialists advise women with diminished oocyte reserve (DOR) that their remaining oocytes probably are of poor quality similar to women of advanced reproductive age. There have been studies, especially employing in vitro fertilization-embryo transfer (IVF-ET), showing very poor live delivered pregnancy rates despite the transfer of morphologically normal embryos in women even with mild DOR. However, other data suggests that the low pregnancy rates are related to the use of high dosages of follicle stimulating hormone (FSH) drugs which down-regulate some key FSH dependent enzymes, cytokines, or proteins required for proper embryo implantation. Some studies have shown that techniques that favor FSH receptor up-regulation, rather than down-regulation, can provide the chance of live delivery 80% as well in women ≤ 35 with DOR, 70% for women 36-39, and 50% for women 40-42. Though some infertility specialists will encourage women whose only infertility issue is DOR, who reject the initial suggestion to consider donor oocytes, to proceed immediately with IVF-ET to maximize success, pregnancies are quite possible with natural conception. Thus, it seems imprudent to make couples undergo the financial burden of IVF-ET in the absence of a significant tubal or male factor problem. Not only have live deliveries occurred in women with DOR, using the principle described to achieve a mature dominant follicle followed by proper luteal phase support, with serum FSH levels over 100 mIU/mL, but also serum Anti-Mullerian Hormone (AMH) levels that were undetectable. This even applies to women in overt menopause where FSH up-regulation was achieved by negative feedback to the pituitary using ethinyl estradiol inhibiting FSH release, or down-regulation of hypothalamic-pituitary stimulation of FSH production by using gonadotropin releasing hormone agonists or antagonists.

Endometrial Assessment · Receptivity Testing

The effect of consecutive cycles of clomiphene citrate therapy on endometrial thickness and echo pattern

Check JH et al., 1995 Obstet Gynecol

To determine whether successive cycles of clomiphene citrate affect endometrial thickness. Thirty-four women presenting for treatment of anovulation, oligoovulation, or follicle maturation defects were given the smallest dose of clomiphene citrate necessary to attain a mature follicle. If no pregnancy ensued, the same dose was continued if a follicle 18-24 mm in diameter and a serum estradiol (E2) level greater than 200 pg/mL were achieved. Ethinyl E2 was supplemented for poor cervical mucus only. Endometrial thickness and echo patterns were measured each cycle at peak follicular maturation. There was no difference in mean endometrial thickness during the first six cycles of therapy, nor was there a trend for thickness to increase or decrease with successive cycles with or without the addition of ethinyl E2. There was no change in the distribution of echo patterns with successive cycles of clomiphene citrate. Post-treatment measures of thickness and echo pattern did not differ from baseline pre-treatment values. The homogeneous hyperechogenic pattern was the rarest. Mean serum E2 and progesterone levels at mid-cycle did not change with successive cycles. One proposed mechanism for the dichotomy between ovulation and pregnancy rates after clomiphene citrate therapy is that the drug adversely affects the endometrium. If clomiphene citrate does affect implantation adversely, the mechanism does not seem to be related to thinning the endometrium or causing an echo pattern that indicates a poor prognosis. The data also suggest that estrogen supplementation does not influence endometrial thickness and would best be used exclusively for hostile cervical mucus.

Preterm Birth · Progesterone Prophylaxis

Increased rate of preterm deliveries in untreated women with luteal phase deficiencies. Preliminary report

Check JH et al., 1992 Gynecol Obstet Invest

Some randomized studies have suggested a significant beneficial effect of 17-hydroxyprogesterone caproate in the prevention of preterm labor [1, 2], The therapy in both studies was initiated at approximately 12-16 weeks and continued until labor. We considered the possibility that a deficient proges terone effect during the first trimester may lead to a higher rate of preterm deliveries. A retrospective study was thus performed comparing the incidence of preterm versus full-term pregnancies in women with luteal phase defects who were either treated or not treated with proges terone supplementation during the first trimester.

Related research

Add-Ons and Adjuncts · Adjunct Evidence Base

Resumed ovarian function and pregnancy in early menopausal women by whole dimension subcortical ovarian administration of platelet-rich plasma and gonadotropins

Hsu CC et al., 2021 Menopause (New York, N.Y.)

This study was designed to investigate if whole dimension subcortical ovarian administration of platelet-rich plasma with gonadotropin, in proximity to most ovarian follicles, is effective in restoring ovarian functions in women during early menopause. Platelet-rich plasma, prepared from 40 mL of autologous peripheral blood using the buffy coat method, was injected into extended subcortical area of bilateral ovaries along with recombinant follicle-stimulating hormone (rFSH) (Gonal-F 300IU) under laparoscopic guidance. The posttreatment ovarian folliculogenesis and serum levels of FSH, luteinizing hormone (LH), and estradiol were followed up for 6 months at weekly to monthly intervals. IVF was carried out in women resuming ovulatory functions. Twelve early menopausal women with mean age of 44.42 ± 2.84 were enrolled. After treatment, 11 women resumed their menstrual period in 37.1 ± 23.5 days. Their average serum FSH was 70.47 ± 20.92 and 26.22 ± 17.55 IU/L, luteinizing hormone was 34.81 ± 11.86 and 14.3 ± 12.8 IU/L, before and after treatment, respectively. The mid-cycle E2 was 251.1 ± 143.8 pg/mL. Ten oocyte retrievals were carried out among six participants, four of them received controlled ovarian stimulation and another two using natural ovulation cycles. Thirteen mature eggs were retrieved which were then ICSI fertilized to obtain 10 normally fertilized 2PN oocytes. Two participants had cleavage stage embryos transferred of which one achieved clinical pregnancy. Whole dimension subcortical ovarian administration of platelet-rich plasma with gonadotropin was shown to restore ovarian functions, at least temporarily, and could increase the probability of pregnancy using autologous oocytes in women with early menopause.

Ovulation Physiology · Follicular Development

Subtle abnormalities in follicular development and hormonal profile in women with unexplained infertility

Lewinthal D et al., 1986 Fertil Steril

A prospective study of six unselected couples diagnosed as having unexplained infertility was done. In three of six patients, subtle abnormalities in follicular development were detected. In the first case poor follicular growth was observed. There was a premature small rise of luteinizing hormone (LH) with subsequent low levels of estradiol (E2) in the late follicular phase and unusual wide LH peak. This was followed by low progesterone levels in the luteal phase. In the second case follicular growth was abrupted by premature LH surge. This surge was triggered by early rise of E2 level while the follicle was still small in size. In the third case luteinized unruptured follicle syndrome was diagnosed, on ultrasound examination. All of the abnormalities were repetitive.

Add-Ons and Adjuncts · Adjunct Evidence Base

Reactivating Ovarian Function through Autologous Platelet-Rich Plasma Intraovarian Infusion: Pilot Data on Premature Ovarian Insufficiency, Perimenopausal, Menopausal, and Poor Responder Women

Sfakianoudis K et al., 2020 Journal of clinical medicine Free full text on PubMed Central

Intraovarian platelet-rich plasma (PRP) infusion was recently introduced in the context of addressing ovarian insufficiency. Reporting on its effectiveness prior to adopting in clinical routine practice is imperative. This study aims to provide pilot data regarding PRP application for ovarian rejuvenation. Four pilot studies were conducted on poor ovarian response (POR), premature ovarian insufficiency (POI), perimenopause, and menopause, respectively. Each pilot study reports on thirty patients, 120 participants were recruited in total. All participants provided written informed consent prior to treatment. Primary outcome measures for the POR pilot study were levels of anti-müllerian hormone (AMH), antral follicle count (AFC) and oocyte yield. For the POI, perimenopausal and menopausal pilot studies primary outcome measures were restoration of menstrual cycle, and Follicle Stimulating Hormone (FSH) levels. A significant improvement on the hormonal profile and the ovarian reserve status was noted, along with improved intracytoplasmic sperm injection (ICSI) cycle performance concerning POR participants. Menstruation recovery was observed in 18 out of 30 POI patients, along with a statistically significant improvement on levels of AMH, FSH, and AFC. Similarly, 13 out of 30 menopausal women positively responded to PRP treatment. Finally, menstruation regularity, improved hormonal levels and AFC were reported for 24 out of 30 perimenopausal women. To conclude, PRP infusion appears to convey promising results in addressing ovarian insufficiency.

Ovarian Hormones · Estrogen

Premature menopause

Okeke T et al., 2013 Annals of medical and health sciences research Free full text on PubMed Central

Premature menopause affects 1% of women under the age of 40 years. The women are at risk of premature death, neurological diseases, psychosexual dysfunction, mood disorders, osteoporosis, ischemic heart disease and infertility. There is need to use simplified protocols and improved techniques in oocyte donation to achieve pregnancy and mother a baby in those women at risk. Review of the pertinent literature on premature menopause, selected references, internet services using the PubMed and Medline databases were included in this review. In the past, pregnancy in women with premature menopause was rare but with recent advancement in oocyte donation, women with premature menopause now have hoped to mother a child. Hormone replacement therapy is beneficial to adverse consequences of premature menopause. Women with premature menopause are at risk of premature death, neurological diseases, psychosexual dysfunction, mood disorders, osteoporosis, ischemic heart disease and infertility. Public enlightenment and education is important tool to save those at risk.

PMID 24848073 24848073 Check et al. 2014, Check 2014