Usefulness of FSH measurements for determining menopause in long-term users of depot medroxyprogesterone acetate over 40 years of age

doi:10.1016/j.contraception.2007.06.005

Contraception

Volume 76, Issue 4, October 2007, Pages 282-286

https://doi.org/10.1016/j.contraception.2007.06.005 Get rights and content

Abstract

Objective

To assess the usefulness of follicle-stimulating hormone (FSH) measurements for determining menopause in 40–55-year-old users of depot medroxyprogesterone acetate (DMPA).

Study Design

FSH levels were measured in 355 blood samples from 82 amenorrheic women during an 18-month period. Blood was collected every 90 days immediately prior to DMPA administration.

Results

Using FSH values >35 mIU/mL as being in the post menopausal range, 32 women (39.0%) presented at least one FSH measurement in the postmenopausal range and 14 of them (43.7%) had more than one elevated FSH measurement and were considered postmenopausal. In five users (15.6%), only the last FSH measurement was within the postmenopausal range, and in 13 women (40.6%), FSH returned to normal values following one measurement that was within the postmenopausal range.

Conclusions

The menopausal status in DMPA users in amenorrhea should be determined based on at least two consecutive high FSH evaluations, since, as shown here, 40.6% of the women with high FSH had a low FSH in the subsequent determination. FSH measurements should be done only in women ≥50 years old because there is a greater possibility of being in postmenopause. However, we do not recommend the interruption of DMPA use prior to the quantification of FSH.

Introduction

Although fertility declines with age during the menopausal transition, there remains a risk of pregnancy during this phase and a need for contraception. Depot medroxyprogesterone acetate (DMPA) is a highly effective contraceptive method used worldwide, with few side-effects and few restrictions to its use, including women in their last reproductive years [1].

DPMA acts mainly by inhibiting ovulation through suppression of the hypothalamic pituitary axis. However, DMPA also causes profound hypoestrogenism [2], [3], with estradiol levels falling below 100 pg/mL in the first 4 months of use, while at the sixth month, the levels are similar to those seen following menopause [3]. Although almost 70% of DMPA users are in amenorrhea after 1 year of use, there is no correlation between the hypoestrogenic status and climacteric symptoms such as hot flashes [3]. Because of the amenorrhea and infrequent climacteric symptoms in users of this method, the diagnosis of menopause can be complicated, making it difficult to determine the moment at which the use of a contraceptive method is no longer necessary.

Some physicians instruct their patients to interrupt use of DMPA in order to determine whether the menstrual pattern has been restored. This interruption is followed by the measurement of follicle-stimulating hormone (FSH) since DMPA has been reported to suppress FSH levels, even after menopause [4], [5], [6]. However, in postmenopausal users of DMPA, FSH is not believed to be suppressed to the levels seen during the reproductive age [6]. If an evaluation of FSH is necessary, the measurements should be done for as long as possible after the last injection or immediately prior to the next DMPA injection [6].

In a recent study, 28.2% of DMPA users over 40 years of age had FSH levels at the postmenopause range (>25.8 mIU/mL) according to the criteria defined by the authors [7]. A second measurement of FSH in some of these women during the following injection cycle confirmed FSH levels above 25.8 mIU/mL at the post menopause [7]. The authors concluded that FSH levels are a good marker for establishing menopausal status in DMPA users. However, their study did not assess the variation in FSH levels during the use of DMPA, particularly with regard to the possibility that a high FSH level could be followed by a low value at the subsequent measurement. In view of the uncertainty surrounding FSH measurements in DMPA users during their final reproductive years, the aim of this study was to measure the FSH levels every 3 months for 18 months in amenorrheic women over 40 years of age who were long-term users of DMPA in order to assess the usefulness of these measurements for determining menopausal status in these women.

Section snippets

Materials and methods

This study was done in the Human Reproduction Unit, Department of Obstetrics and Gynecology, School of Medicine, Universidade Estadual de Campinas (UNICAMP). The protocol was approved by the Institutional Review Board, and all of the women signed an informed consent form prior to enrollment in the study.

All users of DMPA in amenorrhea and ≥40 years of age were invited to participate in the study. Eighty-two women who were long-term users of the injectable contraceptive containing 150 mg of DMPA

Results

Three hundred fifty-five blood samples were obtained from the 82 women. The mean duration of DMPA use was 6.3±4.3 years (range, 9 months to 18 years), and the mean age of the users was 46.0±3.6 years (range, 40–55 years). The mean age of users with at least one FSH result within the postmenopausal range (>35 mIU/mL) was 48.9±2.8 years (range, 43–55 years), compared to a mean age of 44.2±2.7 years (range, 40–50 years) for the 50 users in whom all of the FSH results were within the normal range

Discussion

In menstruating women, the occurrence of amenorrhea for 12 months is generally indicative of menopause [9]. However, this clinical approach to diagnosing menopause is impractical in women using DMPA due to the occurrence of amenorrhea. Although some DMPA users experience hot flashes, others have none of the signs indicative of their menopausal status that are normally helpful in deciding when to stop using this contraceptive; this is a frequent dilemma in women ≥50 years of age [10], [11]. A

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Cited by (14)

Contraception for women after 40: CNGOF Contraception Guidelines
2018, Gynecologie Obstetrique Fertilite et Senologie
La prescription d’une contraception après 40 ans peut parfois se révéler complexe mais elle apparaît indispensable dans cette tranche d’âge puisque la fertilité n’est pas nulle et les risques d’une grossesse non négligeables. Elle nécessite une évaluation globale de la situation en recherchant les différents facteurs de risque vasculaires et métaboliques ainsi que les pathologies bénignes utérines et/ou mammaires déjà présentes.
L’objectif de ce travail était d’élaborer des recommandations pour la pratique clinique concernant la prescription d’une contraception après 40 ans.
Une revue systématique de la littérature en langue française et anglaise, à propos de la contraception après 40 ans a été réalisée sur Pubmed, Cochrane Library. Les recommandations des sociétés savantes internationales ont également été prises en compte (Royal College of Obstetricians and Gynaecologists [RCOG], Faculty of Sexuality and Reproductive Healthcare [FSRH], European Society of Human Reproduction and Embryology [ESHRE], American College of Obstetricians and Gynecologists [ACOG], Society of Obstetrician and Gynecologists of Canada, Center for Disease Control and Prevention, World Health Organization [WHO], Haute Autorité de santé [HAS]).
Aucun moyen de contraception n’est contre-indiqué sur la seule base de l’âge. Cependant, en raison de l’augmentation des facteurs de risque vasculaires et métaboliques avec l’âge, la contraception estroprogestative et le DMPA ne doivent pas être une contraception de première intention. Le dispositif intra-utérin au cuivre et les progestatifs (voie orale, sous-cutanée, intra-utérine) sont à privilégier car ils offrent une contraception efficace avec de faibles risques de complications.
La contraception des femmes de plus de 40 ans ne doit pas être négligée. Les contraceptifs de longue durée d’action et les microprogestatifs oraux sont à proposer en première intention. Les patientes dont la contraception est non hormonale pourront l’arrêter après 1 an d’aménorrhée au-delà de 50 ans. Les femmes traitées par contraception estroprogestative devront l’arrêter à 50 ans. Les dosages hormonaux réalisés chez les femmes utilisant une contraception hormonale ne sont pas recommandés. Une fenêtre thérapeutique doit être proposée en maintenant une contraception par méthode barrière. En cas de persistance d’une activité ovarienne, une contraception non hormonale ou progestative (hors DMPA) pourra alors être mise en place ou reprise.
Choosing contraception for women over 40 can be sometimes difficult but it is crucial since fertility and pregnancy's risks still exist. It requires a thorough evaluation of the situation, in order to identify any vascular and metabolic risk factors, along with the uterine and mammary benign pathologies already diagnosed.
The objective of this review was to elaborate some guidelines for clinical practice regarding contraception's prescription for women over 40.
A systematic review of the French and English existing literature was conducted. Pubmed and the Cochrane library were used to identify studies about contraception for perimenopausal women. International guidelines published by scientific societies were also reviewed (RCOG, FSRH, ESHRE, ACOG, WHO, HAS).
No contraceptive methods are contraindicated on the sole basis of age alone. However, because age is a risk factor for vascular and metabolic diseases, combined hormonal contraception and DMPA should not be prescribed at first intention. Copper IUD and progestin-only contraceptives (pill, implant, intrauterine device) should primarily be considered, since they offer good efficacy with lower risks.
Contraception for women over 40 should not be put aside. Long acting reversible contraception and progestin-only pill have to be prescribed as first-ine. Contraception is no longer needed for women over 50 who use non-hormonal contraception, after a 12 month-amenorrhea. Patients treated with combined hormonal contraception must stop using it over 50. Measuring hormonal levels while using hormonal contraception is not recommended. An hormonal-contraception-free interval must be considered, while using barrier contraception method. If an ovarian activity persists, a non-hormonal contraception or progestin-only contraception (except for DMPA) should be (re-)established.
Contraception during the perimenopause
2013, Maturitas
Citation Excerpt :
While FSH is suppressed by DMPA during the initial phase of the injection cycle, FSH should return to baseline values by at least 80 days post-injection [74]. The usefulness of FSH in diagnosing menopause in long-term users of DMPA was evaluated in a Brazilian study [75]. Women over age 40 (mean age 46, range 40–55) who were amenorrheic on DMPA (n = 82) had two serial evaluations of serum FSH, at baseline just before a subsequent injection and 90 days later.
Although the absolute risk of pregnancy is lower during the perimenopause due to decreased fertility and decreased coital frequency, unintended pregnancy occurs at ratios similar to those observed in young women, and pregnancies that do occur are at high risk for maternal complications and poor outcomes such as miscarriage or chromosomal abnormalities. Therefore all premenopausal women should receive counselling that includes discussion of sexual habits and contraception during routine health care encounters. The majority of US women in this age group use permanent contraception, but other methods can be safe and effective and can have non-contraceptive benefits.
No contraceptive method is contraindicated based on age alone. However, estrogen-containing methods should be reserved for women without cardiovascular or thrombotic risk factors. The levonorgestrel intrauterine system (LNG-IUS, Mirena^®) has particular benefits during perimenopause and is safe for use in nearly all women. The LNG-IUS is approved for treatment of heavy menstrual bleeding, a common concern during the perimenopause. A substantial literature supports the use of the LNG-IUS for endometrial protection during transition from contraception to hormone therapy, although this is off-label in the United States.
Reliable contraception should be used until menopause is confirmed either by cessation of menses for 2 years prior to age 50, for 1 year after age 50, or by two elevated follicle-stimulating hormone (FSH) values ≥20–30 IU/l while off hormonal methods for at least 2 weeks. Sterility cannot be assumed until at least age 60 because spontaneous pregnancies have been reported in women up to age 59.
Serum anti-müllerian hormone level is not altered in women using hormonal contraceptives
2011, Contraception
Citation Excerpt :
The guideline suggested that FSH assessment is not reliable for combined contraceptive users even if measured in the pill-free interval, but it can be used for POC users based on a reported study showing that FSH elevation was still evident in POI users [10]. However, there was a more recent report [14] that FSH levels fluctuated with the days in relation to injections, and over 40% of women using POI gave inconsistent results on repeated FSH measurements. Although the authors did not dispute the use of FSH test for this purpose, they suggested restricting it only to women aged 50 or above, in recognition of the limitation as mentioned.
Anti-müllerian hormone (AMH) is secreted from granulosa cells of antral follicles into the circulation of adult women and hence could serve as an ovarian function test. This would be of value to hormonal contraceptive users if its serum level is unaffected by the use of hormonal contraceptives.
We prospectively recruited 95 women using combined oral contraceptive (n=23), combined injectable contraceptive (n=23), progestogen-only pills (n=9), progestogen-only injectable (n=20) and levonorgestrel intrauterine system (n=20), and measured their serum AMH concentration before and 3–4 months after treatment.
No significant difference in pre- and post-treatment serum AMH level was evident in all the treatment groups studied.
Being unaffected by hormonal contraceptives, serum AMH measurement is potentially a useful clinical test in hormonal contraceptive users for the differential diagnosis of anovulatory disorders and determination of menopause.
Forearm bone mineral density in postmenopausal former users of depot medroxyprogesterone acetate
2008, Contraception
Citation Excerpt :
Weight and height were measured and recorded prior to BMD measurement. In the group of DMPA users, age at menopause was defined as the day on which FSH measurement was found to be above 40 mUI/mL [15] and in the control group in accordance with the date of the woman's last menstrual period. BMD was the dependent variable and was defined as the ratio between bone mineral content and the area of the bone measured (g/cm2).
The aim of the study was to compare the bone mineral density (BMD) of postmenopausal women who had used depot-medroxyprogesterone acetate (DMPA) or a copper intrauterine device (IUD) as a comparison group until menopause.
BMD was measured using dual-energy X-ray absorptiometry at the nondominant forearm for up to 3 years following menopause in 135 women aged 43–58 years: 36 former DMPA users and 99 former IUD users.
Mean duration of use was (mean±SEM) 9.4±3.8 and 14.7±6.2 years for the DMPA and IUD groups, respectively. One year after menopause, mean distal radius BMD was 0.435 and 0.449 in DMPA and IUD users, respectively, and 0.426 and 0.447 at 2–3 years following menopause. Ultra-distal BMD was 0.369 and 0.384 in DMPA and IUD users, respectively, at 1 year, and 0.340 and 0.383 at 2–3 years.
At 1 and 2–3 years following menopause, no significant differences were observed in the BMD of postmenopausal women aged 43–58 years, who had used DMPA or an IUD until menopause.
Contraception in women over 40 years of age
2013, CMAJ. Canadian Medical Association Journal
Citation Excerpt :
Observational studies have consistently shown that average follicle-stimulating hormone (FSH) levels increase in perimenopausal women as age increases, but individual levels can vary over time. These hormone levels are not suppressed substantially during DMPA use, but similarly they may be an unreliable signal of menopause in younger users.75–77 Two studies showed that FSH levels were significantly suppressed in women who were using estrogen-containing oral contraceptives and may not rebound until 2 weeks after the last active pill;77,78 therefore, FSH measurement during oral contraceptive use may not be reliable in determining menopausal status.
Contraception During Perimenopause: Practical Guidance
2022, International Journal of Women's Health

View all citing articles on Scopus

^☆: This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (grant no. 03/08391-7).

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Original research articleUsefulness of FSH measurements for determining menopause in long-term users of depot medroxyprogesterone acetate over 40 years of age☆

Abstract

Objective

Study Design

Results

Conclusions

Introduction

Section snippets

Materials and methods

Results

Discussion

Contraception

Contraception

J Steroid Biochem

Contraception

Fertil Steril

Am J Obstet Gynecol

Maturitas

Maturitas

J Steroid Biochem Mol Biol

Contraception

Fertil Steril

Lancet

Am J Obstet Gynecol

Original research article
Usefulness of FSH measurements for determining menopause in long-term users of depot medroxyprogesterone acetate over 40 years of age☆