Gautam N. Allahbadia and Markus Nitzschke (eds.)Minimal Stimulation and Natural Cycle In Vitro Fertilization10.1007/978-81-322-1118-1_7

7. Ovarian Stimulation in Patients with Ovarian Insufficiency

Markus Nitzschke¹

(1)

Department of Assisted Reproduction, Obstetrics and Gynecology, ICI – Instituto Canario de Infertilidad, Calle León y Castillo, 294, Las Palmas de Gran Canaria, C. P. 35005, Spain

Markus Nitzschke

Email: markus@icinfertilidad.com

Abstract

In general, patients with low ovarian reserve are difficult to manage and have a relatively poor prognosis. Hormonal changes due to ovarian insufficiency can influence and change the individual menstrual cycle pattern of each patient over time, which may result in difficulties to conceive naturally. Observing the menstrual cycle pattern of patients with low ovarian reserve, it is possible to distinguish different stages of ovarian insufficiency. All clinical stages can be treated by a simple medical treatment, based on oral contraceptive pills, ethinyl estradiol, and Clomiphene citrate, with or without the combination with modified natural cycle in vitro fertilization (IVF). Experience shows that ovulation can successfully be controlled by the use of Clomiphene citrate and does not necessarily require gonadotropin-releasing hormone (GnRH) analogs for pituitary suppression. This knowledge opens a new space for development of alternative protocols respecting the patients’ own physiology with no need for heavy stimulation. Patients with ovarian insufficiency may benefit from this approach, which can be offered before referring them to egg donation.

Keywords

Low ovarian reserveClomiphene citrateNatural cycle IVF

Introduction

Treating infertility patients with low ovarian reserve is one of the most frustrating and challenging tasks that infertility specialists can encounter in their practice. These patients usually show strange menstrual cycle patterns. They do not respond normally to ovarian stimulation regimens, and they often develop treatment-resistant ovarian cysts. The percentage of infertility patients with low ovarian reserve is growing in all infertility practices in the developed world, due to a growing older population, and the decision of many women to start reproduction in their mid-30s. In some areas, especially in bigger cities, the percentage of patients with low ovarian reserve exceeds 50 % in most infertility practices. Despite the urgent need for new treatment regimens for this patient population, very few groups are undertaking serious research in this field. For lack of better options, many infertility specialists simply refer those patients to egg donation.

Inspired by a publication from Japan (Teramoto and Kato 2007), our group started to look for alternative treatment options for this particular patient group. We used the most empirical approach possible. We went back to pure observation of our patients’ cycles, trying to understand their individual hormonal pattern. After observation of hundreds of menstrual cycles, we were able to classify four different types of ovulation in women with low ovarian reserve. We called them “compensated stage,” “stage of desynchronized menstrual cycle,” “stage of pathologic premature LH rise,” and “stage of suppressed follicle growth.” In a second step, we used an adaptive treatment approach on each ovulation group. The different treatments were based on our personal experience, and different approaches described in the literature, mainly those of Teramoto (Teramoto and Kato 2007).

The stimulation protocol for IVF, which has been described by Teramoto and Kato in their publication from 2007, involves the use of 50 mg Clomiphene citrate from cycle day 3 onwards. This new protocol is designated as “minimal ovarian stimulation.” It is not designed for women with low ovarian reserve in particular. Clomiphene is administered in this method for a relatively long period of time, i.e., 10–12 days until the day before maturation is triggered by administration of a GnRH agonist. Oocytes are then retrieved 32–35 h later. By this method, Teramoto makes use of the antagonistic action of Clomiphene citrate to the estradiol receptor on the hypothalamus level, inhibiting both positive and negative feedback and resulting in the induction of the ovarian stimulation and suppression of ovulation.

The other main inspirations for a new treatment approach for patients with low ovarian reserve came from a group in New Jersey, USA (Check et al. 1990). They used ethinyl estradiol to bring high FSH levels down to normal levels. As we will explain later in this chapter, very high FSH and LH levels tend to downregulate the FSH receptors on the antral follicles and prevent follicle growth. If serum FSH levels can be reduced to physiological levels, using ethinyl estradiol, the receptors can recover and follicle growth and ovulation can be restored.

The new treatment approach that we have developed was mainly based on the natural cycle of the patients. The usual medication we used in these cases was Clomiphene citrate only to control ovulation, the way it was already described in the publication from Teramoto and Kato. In other patients with ovulation disorders, we successfully applied ethinyl estradiol, combined oral contraceptive pills, or Clomiphene citrate depending on the pathology. The following observations and description of protocols are not evidence-based and rely only on the empiric experience of our group. Nevertheless, using our approach, we managed to have pregnancies and live births in nearly menopausal women and other “hopeless” cases, which were originally referred to egg donation.

In 2011, we performed a proof of concept study with 10 patients at the Instituto Mexicano de Infertilidad in Guadalajara (Mexico), a private IVF clinic. Patients were informed about off-label use of the medication. The local Ethics Review Committee approved the study protocol, and a written informed consent was obtained from all patients. Ten patients with AMH <1.0 nmol/L and severe cycle disorders due to ovarian insufficiency were observed over an 8-month period. Patients were 22–42 years old (average 39.3). Blood samples were drawn to determine FSH, LH, E2, and transvaginal ultrasound scans were performed on different days of the cycle. Depending on the cycle pattern of each patient, we offered individualized treatment approaches based on natural cycle IVF using Clomiphene to control ovulation as described by Teramoto (Teramoto and Kato 2007), GnRH agonists to induce ovulation and either ethinyl estradiol or combined oral contraceptive pills to regulate the cycle. Embryos were vitrified in day 2 stages and transferred later in artificial cycles.

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